FROM: Chiro Res J 1988; 1 (1) Spring: 21–46 ~ FULL TEXT
Charles A. Lantz, Ph.D., D.C.
Sid E. Williams Research Center
Life Chiropractic College
The literature was reviewed concerning the effects of joint immobilization on the degeneration of articular and periarticular connective tissue. Every connective tissue component of an articulation is affected by immobilization, and each major component
is discussed individually; these include the articular cartilage, synovium, articular capsule, periarticular ligaments, subchondral bone, the intervertebral disc and the meninges.
Particular emphasis was placed on changes in the biochemical constituents of connective tissue, collagen, proteoglycans and hyaluronic acid, and the relation of these changes to alterations in the functional and biomechanical properties of the tissues. Thus an attempt is made here to establish a molecular basis for the theory and practice of chiropractic.
Each connective tissue component has its own pattern of degeneration and each contributes in its own unique way to joint stiffness following immobilization. Of particular significance to chiropractic is the observation that many of the changes observed following immobilization are reversible upon remobilization of the joint within a reasonable period of time. The time course of events in the degenerative process is significant in this regard and is discussed in detail. The reported changes are evaluated in light of the five components of the vertebral subluxation complex: kinesiopathology, neuropathology, myopathology, histopathology and biochemical abnormalities. In particular, the relation between the degenerative process and neurological elements associated with the spinal joints is discussed. The relation of spinal mobility to immobilization studies performed on extremities is discussed, as well as the extrapolation of results from animal experiments to the human condition. Recommendations are presented for future directions in research on the issue of subluxations and chiropractic adjustive procedures.
Since the development of the fixation hypothesis by Dr. Henri Gillet  motion palpation has become one of the most widely used analytical procedures in chiropractic practice. This work systematized what chiropractors had practiced for years, and won wide acceptance among students and practitioners alike. Articular 'fixations' are almost universally recognized as a significant if not major, component of the chiropractic subluxation complex [2, 3]. There is little known, however, about the nature of the fixation process, nor is there a description of its physiological and pathological aspects from a chiropractic perspective. In this paper, a detailed description is provided of the degenerative changes known to occur upon immobilization of an articulation and it is proposed that these changes represent a reasonable model for the fixation component of chiropractic subluxations.
The basis of the proposed model is the well known and extensively documented fact that when a joint is immobilized, a very predictable pattern of degeneration ensues [4, 5]. It is because of this degenerative process that immobilization continues to be one of the primary tools for investigating osteoarthritis [6, 7, 8]. It is now well recognized, however, that the degeneration which occurs upon immobilization differs significantly from that seen in osteoarthritis  and is therefore of limited usefulness in modeling this condition. Studies show, however, that articular degeneration is a real and predictable sequel to immobilization. This, together with the recent observations of Sato and Swenson  that spinal movement will elicit a predictable pattern
of visceral sympathetic output, implies that spinal mobility of a general nature may be significant in the maintenance of normal autonomic and neuromuscular tone.
Of particular significance to the proposed model is the development of stiffness in a joint which has been immobilized [10–13]. The changes in a joint upon immobilization involve every structural component of the joint, from callous subchondral bone to the synovium, from meninges to ligamentum flavum [4, 6, 10, 11, 14–16]. For descriptive purposes, I have divided the presentation into the distinct connective tissue elements which are affected by immobilization and will discuss each individually.
The most notable effect of immobilization degeneration, and the characteristic most responsible for its use in modeling the degenerative changes of osteoarthritis is alteration of the articular cartilage . The articular surfaces are normally smooth and regular with a glassy appearance, but when degenerated, they lose this hyaline luster, and become duller and chalky . Articular cartilage has a characteristic cellular distribution and matrix composition  the structure of which is quite complex [18, 19].
There are regional differences in molecular composition of the cartilage which make it suitable for the functions it serves in joint dynamics [20, 21]. For instance, the surface layer is a more densely packed and highly ordered network of collagen fibers
with much less proteoglycan than is found deep toward the subchondral bone . There are also regions of highly ordered collagen fibers deeper within the cartilage . Cartilage itself is avascular , which has the effect of largely isolating the cartilage tissue metabolically from the remainder of the organism .Separating the cartilaginous layer from the cancellous layer from the cancellous bone in the adult is a thin plate of dense crystalline mineral deposit which effectively seals the cartilage from the bone compartment beneath . The articular surface of the cartilage is bathed in synovial fluid with which it exchanges waste and nutrients . In the immature joint, the cartilage may also be nourished from the subchondral bone [24, 25]. The relation of articular cartilage to synovium is significant from the standpoint of pathogenesis because of exposure to synovial enzymes and cellular elements, both inflammatory and infective, which arrive at the articular surface via the synovial fluid .
In general, cartilage can be described as a gelatinous matrix of collagen fibrils which are relatively immature; that is, they consist of individual fibrils, with only few large fibers. The interspace between individual fibrils are filled with highly
charged anionic proteoglycan molecules  entangled in the collagen network. The dense population of fixed negative charges attract smaller, more mobile cations such as sodium and potassium , as well as calcium . It is believed that proteoglycans are involved in the regulation of calcification of cartilage [29, 30]. The localized high concentration of small ions increases the osmotic pressure in the collagen interstices and attracts water into the collagen matrix  creating the tissue swelling pressure .In fact, about 75% of the weight of the cartilage is water [23, 32]. Collagen, on the other hand, accounts for the tensile strength of cartilage [33, 34]. This high tensile strength restrict the extent of swelling caused by the strong osmoti
c pressure within the interstices.
This balance of forces is believed to account for the stiffness of cartilage  and provide adequate turgor to support the hydraulic function of the joint surfaces . When water from interstitial fluid is displaced by a comprehensive force, proteoglycans remain fixed within the matrix and draw water back when the load is removed . This gives cartilage a resiliency resembling biological spring . It has been shown  the proteoglycans contribute to the stiffness of cartilage and that in degenerate cartilage there is a softening which correlates with decreased proteoglycan content [33, 37].
DEGENERATIVE CHANGES IN ARTICULAR CARTILAGE IMMOBILIZATION:
Degenerative changes in the articular cartilage following immobilization depend upon whether the cartilage is in a area opposed by other cartilage or in an unopposed area . In the opposed areas there is a decrease in glycosaminoglycan content associated with immobilization, while in the unopposed ares, glycosaminoglycan (GAG) content actually increases. Measurable changes in chondrocyte activity are apparent within one day of immobilization , describe as an increase in colloidal iron staining of the chondrocytes . By the second day of immobilization, there is a noticeable decrease in the metachromatic staining, indicative of proteoglycan loss. The loss of proteoglycans correlated with a decrease in cation and water content within the matrix, and a decrease in the total mass and volume of the cartilage . By the third day, degenerative changes are seen in chondrocytes in the areas of contact between opposing articular surface, and by day four, there is a mark decrease in proteoglycan content of the matrix . Within six days, in the rat, there was an almost complete loss of metachromasia, indicating loss of proteoglycan . By 15 days immobilization in rats, there was a flattening of the opposed cartilage surface, and a mark loss of chondrocytes in the opposed cartilage; by 45 days, there were adhesions between the articular cartilage and the menisci . Also, by 45 days, there was marked cyst formation in the cartilage which developed into ulceration; by 90 days these had penetrated the subchondral bone . In human cadavers, Harris and MacNab  describe degenerative zygapophyseal joints with fibrous adhesions varying in extend from single strands to dense mats which preclude all movement of the joint.
FUNCTIONAL CHANGES ASSOCIATED WITH IMMOBILIZATION DEGENERATION:
The first and most significant sign of immobilization degeneration is a softening of the cartilage described as a decrease in comprehensive stiffness [35, 41], or increase deformability . This property has been correlated with the loss of proteoglycans from the matrix [33, 37, 41, 42]. Tensile strength, which is the parameter affected by the composition and organization of collagen , is not affected by loss of proteoglycan . Collagen is also responsible for resting shear stresses  so there is little change in this parameter until later stages of degeneration.
MOTION VERSUS JOINT LOADING:
While the evidence cited above supports the idea of immobilization leads to degenerative changes in articular cartilage, the converse is not true; it is clear that mobility alone is not capable of sustaining articular cartilage. Marshall et al.  has shown that unrestricted joint motion, in the absence of normal loading of the joint, does not maintain normal articular cartilage, and leads to marked loss of metachromasia and a 56% decrease in cartilage thickness after four weeks. Persistent pressure, on the other hand, leads to degenerative changes more closely resembling those seen in osteoarthritis, especially fibrillation and vascular invasion with subchondral involvement . Release of the compressive forces and remobilization resulted in continued degeneration of the articular cartilage . Obviously, the more severely damaged the cartilage, the less likely it is to regenerate. On the other hand, Thaxter et al.  found that weight-bearing in the absence of joint mobility led to a slightly accelerated degeneration of articular cartilage compared to immobilized, non-weight bearing joints.
Ligaments consist primarily of collagen fibers arranged in parallel bundles with interspaces filled with proteoglycan. In contrast to cartilage, however, the ratio of collagen to proteoglycan is much greater [100-1000:1] in ligaments and other fibrous connective tissue than in cartilage . Proteoglycans have been ascribed several functions in ligaments, among which are: 1( to provide internal lubrication for the collagen fibrils and fibers as they slide across one another [47,48], 2) maintain a critical interfiber spacing necessary to prevent anomalous collagen fiber crosslinkage formation , 3) to provide physical crosslinkages between individual collagen fibrils  and 4) to help organize collagen fibrils in tissue-specific patterns [36, 49]. Thus whereas collagen fibers themselves are virtually inelastic, ligaments have a gross deformability, and can stretch to a certain degree .
When discussing ligaments in relation to joint immobilization, it is necessary to distinguish periarticular ligaments, such as collateral ligaments of the knee, from intra-articular ligaments, such as the cruciate ligaments. The ligamentum flavum is distinctively different from either of the two aforementioned ligaments due to its high elastin content , and the joint capsule, a ligaments in the strictest sense, differs from any other connective tissue structures . Due to its unique structural and functional characteristics, the capsule will be considered in a separate section below. Because of the marked differences in composition, structure and local environment of each ligament type, it is likely that there are significant differences in their responses to immobilization. Thus in this section, ligaments are discussed individually in the broader consideration of the effects of immobilization on ligaments.
Changes on Immobilization and with Activity:
When a joint is immobilized, the first detectable change in ligaments is a decrease in proteoglycan content accompanied by a decrease in hyaluronate and water [15, 52]. In medial collateral ligaments of rabbit knees immobilized in extension, there was an
increase in GAG concentration  as indicated by uronic acid and hexosamine content or by an increase in radiolabled sulfate uptake . Kinetic studies using radiolabled sulfate  indicate an increase in the rate of GAG synthesis. Immobilization in flexion, however [12, 15, 47], leads to a decrease in GAG content and tissue water in the periarticular fibrous connective tissue of rabbits and dogs. While there is no change seen in collagen mass in periarticular connective tissue from immobilized joints, whether immobilized in flexion or extension [5, 12, 15, 38, 47], it has been shown  that collagen turnover is increased. On the other hand, Klein et all  report a significant decrease in collagen content of the anterior cruciate ligament and lateral meniscus following immobilization. These studies must be compared with the findings of Tipton et al  who found no difference in collagen content in ligaments from dog knees which were immobilized, compared to normal controls, but a significantly increased collagen content in animals which had been repeatedly exercised. These same authors, using rather crude analysis under light microscope, concluded that the collagen fiber diameter was greatest in the exercised animals, and least in ligaments from animals which had been immobilized. Electron microscopic analysis of collagen fiber diameter, however, indicated an increase in fiber size in ligaments from immobilized joints .
It is well recognized in orthopedics that a sequel to immobilization is joint stiffness . One mechanism used to explain this is ligamentous contracture , which is essentially a shrinking of the ligament, a form of atrophy. Since proteoglycans occupy a significant volume of the tissue, a reduction in their levels allows the collagen fibers to approach each other more closely. Evidence for this is the observation of decreased ligament volume and an increase in the diameter of collagen fibrils in medial collateral ligaments from immobilized rat knees . As the collagen fibers approach each other, they are believed to form cross-linkages by condensing lysine residues in adjacent collagen fibrils . These newly-formed molecular bridges presumably stabilize the ligament in its acquired conformation to support and stabilize the joint in its new dynamic range of movement . When adequate proteoglycan is maintained between collagen bundles, the fibrils cannot approach closely enough to connect molecularly. On the other hand, proteoglycans themselves form linkages between collagen fibers and contribute thereby to the tensile strength of the ligament overall . The chemical nature of the linkages will, of course, be different when lysine is the linking agent, compared to proteoglycans, and the effect on ligament function would similarly by expected to differ significantly.
FUNCTIONAL CHANGES FOLLOWING IMMOBILIZATION:
The effect of the biochemical changes mentioned above on the ligaments is to alter their mechanical properties to stress. Binkles & Peat  have demonstrated a decrease in linear stress, maximum stress and stiffness of ligaments from rat knees immobilized in flexion. According to these authors, in immobilized joints, ligament laxity and mechanical failure may occur at relatively low levels of force, compared to normal ligaments. However, due to the increase in compliance (stretch) of ligaments following immobilization, it appears that factors other than ligament stiffness are responsible for gross joint stiffness , such as intra-articular adhesions, contracture of the joint capsule, or muscle shortening. Similar results were obtained by Woo et al.  using medial collateral ligaments from rabbit knees immobilized in flexion. There was an approximately 66% decrease in ligament stiffness, ultimate load and energy absorbing capacity of the ligament-bone units from immobilized knees. Using anterior cruciate ligaments from the limbs of primates immobilized at 90 degrees flexion, Noyes et al. [57, 58] showed a significant decrease in maximum failure load (ligament strength) and energy absorbed to failure, 39% and 32%, respectively, compared to control animals. They also found an increase of about 29% in ligament compliance, which corresponds with a decrease in stiffness. After 20 weeks of remobilization, there was a partial return of ligament strength and a complete recovery of ligament compliance to normal levels. It is notable that these authors found no significant changes in cross sectional area of the ligaments at their midpoints after immobilization. This was confirmed in other studies , but there was a significant decrease in the volume of immobilized ligaments.
In related studies on the effect of immobilization or activity on the repair of ligaments , all measured parameters were improved by activity, and all were impaired by immobilization. There was a significant increase in wet and dry weights of injured ligaments which were allowed to repair under conditions of exercise, as compared to non-exercised controls, or immobilized joints. Collagen synthesis and DNA content were similarly increased by exercise and decreased by immobility. Separation force, the force required to rupture the ligament, was increased in ligaments repaired under the influence of exercise, and decreased under immobilization conditions when compared to controls.
The articular capsule of synovial joints consists of dense fibrous connective tissue which is less highly organized than that of tendons and ligaments . It is, however, ligamentous in structure , with a similar proportion of collagen and proteoglycan . The capsule is lined with the synovial membrane which is highly vascular and responsible for maintenance of the synovial fluid, discussed below. Attached to the capsules of the spinal articulations are the ligamenta flava ventrally and the tendons of the multifidi on the dorsal side , so it is difficult to consider the capsule without also considering these structures. The capsule is known to resist spinal flexion more than any other movement , and it experiences more strain in rotation than any other paraspinal ligament . The tensile strength of the capsule decreased with age, so that tears in the capsule are more easily provoked. It has been shown that the capsule thickens in joints affected by osteoarthritis [5, 16]. In studies on joint stiffness following immobilization it was clearly demonstrated that capsule contracture contributed significantly to the observed stiffness , and increasingly so the longer the joint is immobilized.
When a joint is immobilized, the effect on the capsule appears to depend upon the tension on the capsule in the immobilized sates and may well differ diametrically on one side of a joint compared to another as is known to occur in the IVD of scoliotic spines [63, 64]. This would not be surprising since it is already known that the more distal part of the lumbar zygapophyseal capsule is stretched more than the more proximal part during flexion . When a joint is immobilized in extension, the capsule is reported to thicken and shorten [5, 38], and this is accompanied by an increase in proteoglycan content and synthesis . When immobilized in flexion, there is definite evidence of joint contracture with a decrease in overall thickness and mass of the capsule . This is accompanied by a decrease in proteoglycan synthesis and tissue content [12, 38]. The extent of contracture is directly correlated with the length of immobilization in experimental animals . It is also of interest to note that immobilization of rabbit knees resulted in thickening of the ipsilateral hip joint articular capsule, as well as the knee joint capsule . Shortening and thickening of the articular capsule has been hypothesized to increase pressure on the cartilage of the joint, and thus contribute to cartilage damage [38, 62]. This may implicate the articular capsule as a more primary factor in the development of osteoarthritis  than merely a secondary effect as is usually stated.
In the normal rat knee, both articular surfaces are convex to the joint space, and dynamic stability is provided by the menisci which, in sagittal section, form wedges whose apices point toward the center of the joint space . In the spine, there appear to be no true menisci, but in the more mobile regions of the spine there are small meniscoids, invaginations of the synovial membrane which serve a function similar to the menisci of other joints . The meniscoids have received some attention as etiological components in the development of subluxations , or of 'acute locked back' . The mechanisms described are usually biomechanical, involving meniscoid entrapment .
Upon immobilization of extremities, morphological changes in the menisci resemble those of the articular cartilage ; changes in cellular distribution of chondrocytes are seen from a homogeneous laminar distribution to clumping of chondrocytes at areas
of contact and an increase in metabolic activity. Prolonged immobilization leads to ulceration of the meniscus cartilage with fusion to the articular surface, forming a continuous cartilaginous bridge which, upon remobilization of the joint, may persist as a completely formed ligamentous connection between articular cartilage and the meniscus . Clinically, these persistent pseudo-ligaments could restrict joint movement in ways which are unpredictable and difficult to diagnose. Biomechanically, when rabbit knees were immobilized in flexion, there was a decrease in the concentration of glycosaminoglycan in the menisci , whereas collagen content remained unchanged when compared to control limbs. In osteoarthritic menisci however, there appears to be an increase in GAG, but a decrease in the collagen content in areas of degeneration while in rheumatoid arthritis there is a decrease in both proteoglycan and collagen in degenerated areas .
SYNOVIUM AND SYNOVIAL FLUID:
With immobilization, the changes in the synovial fluid are characteristic and predictable [4, 14]. The earliest detectable histological changes in the study by Evans et al  were changes in the synovium. Upon immobilization, the synovium develops a hyperemia followed by increased cellularity and later by subsynovial fibrosis . The synovial space becomes infiltrated with fibrofatty tissue which obliterates the joint cavity . This is later replaced with mature fibrous tissue which obliterates the joint cavity . This is later replaced with mature fibrous tissue which begins to erode or replace the articular cartilage. Prolonged immobilization results in complete replacement of the articular cartilage with fibrous tissue. Subsequent calcification leads to complete osseous fusion of the joint. Clinical studies on the human spine  support this sequence of events in spinal synovial joints. Remobilization of a joint which has undergone fibrofatty consolidation of the synovial space can result in the formation of a new joint cleft  lined with fibrofatty tissue and which will develop a new synovial membrane. Adhesions often form between the fibrotic tissue in the synovial space and the articular cartilage. These may persist even after remobilization of the joint .
Biochemical changes in the synovial fluid have been examined in relation to degenerative changes in arthritic joints, particularly related to rheumatoid arthritis[68, 69]. Since the latter is believed to be an autoimmune disorder, and antibodies to collagen are found in high titer in the serum of rheumatoid patients , these studies have focused on the relationship between collagen degeneration by collagenase and the evolution of rheumatoid arthritis. Collagenase activity has, in fact, been isolated from the synovial fluid of joints affected by rheumatoid arthritis , and the degree of inflammation and degradation has been correlated with the levels of collagenase in the synovial fluid of rheumatoid arthritis patients . Synovial collagenase is also found in fluid from joints afflicted by osteoarthritis and other joint diseases, and is thus not pathognomonic for rheumatoid arthritis. Other enzymes have been studied from the synovium of arthritic joints as well. A group of enzymes known as cathespins are known to digest proteoglycans in human articular cartilage . It has been suggested that the cathespins play an important role in the development of human arthritis . The actual source of these enzymes appears to be from cellular elements of the blood which infiltrate the synovium [74, 75]. In other studies on polychondritis, there was identified a cellular immunity to cartilage proteoglycan , with a striking absence of humoral (antibody) immunity.
It was once believed that bone, because of its gross structural integrity, was metabolically inert. We now recognize, however, that bone is metabolically quite active and readily undergoes plastic remodeling in response to altered patterns of stress in the body. The role of piezoelectric currents within the bone are now well recognized as contributing factors in this process . These currents vary depending on the stress patterns of the bone, and there is undoubtedly a change in stress patterns on a bone when its associated joints are immobilized.
The effect of immobilization or disuse on bone mineralization is well documented. Generalized disuse osteoporosis is seen in prolonged bed rest , in the weightlessness of space  and in hibernation. Regional bone mineral loss can be the result of localized immobilization (splinting) as follows trauma . Disuse osteoporosis has been shown to be associated in many cases with hypercalcemia . Immobilization has been shown  to weaken the insertions of ligaments into the bone. There are two modes of ligamentous attachment to bone ; directly into the bone via the periosteum, or via a fibrocartilagenous plate. The effect of bone resorption on the mechanical failure of ligaments at the insertion site depends upon the type of osseous attachment , there being a greater effect at the site of direct ligament-bone connection. The fibrocartilage plate characteristic of certain ligament attachments provides some degree of protection against ligament-bone failure. Thus, in a joint which has been immobilized for some time, ligaments would be much more prone to avulsions at their osseous insertions . Histological studies have shown a decrease in trabecular bone mass at the site of ligamentous insertion which is greater than similar changes in the shaft on the same bone .
When immobilization is accompanied by persistent pressure, the degenerative changes occurring in subchondral bone resemble those of osteoarthritis [45, 84], with substitution of the subchondral bone with fibrous tissue and vascular proliferation into the cartilage. Evans et al  described subchondral lesions in every instance of cartilaginous degeneration in rat knees, but such findings were inconsistent in similar work by Thaxter et al. . In the spine, the subchondral spongiosa bone of the vertebral bodies bears a different relationship to the cartilage of the end plate than does the cancellous bone of diarthroidal synovial joints, such as knee cartilage or articular cartilage of the zygapophyseal joints; nutrients for the cartilage of the end plate, as well as for the nucleus pulposus and inner annular fibers, must originate from the vascular beds of the subchondral bone of the vertebral bodies . Therefore, any change from the optimal state may be reflected in the marked predisposition to degenerative damage that is characteristic of the aging disc. The health and integrity of the overlying articular cartilage depends on the mechanical properties of its bony bed .
INTERVERTEBRAL DISK (IVD):
Although many studies deal with degenerative changes of the discs[87--94], there were no studies found concerning specifically the effect of immobilization on the IVD. It is of interest to discuss the degenerative changes which has been described in the IVD,as they parallel changes in other connective tissues seen upon immobilization.It is generally presumed that degenerative changes of the disc lead to immobilization and degeneration, rather than the converse.For instance,changes has been described in the articular cartilage of the spinal zygapophyses following immobilization of a vertebral motor unit by vertebral fusion following disc degeneration [87,88,95], as well as changes in adjacent discs when a particular disk is fused in experimental animals. However,recent observations on patients undergoing surgery for prolapsed disc whose symptoms had not responded to chiropractic adjustment suggest that immobilization or restriction of spinal movement may contribute to degeneration of the disc.It has been observed clinically that in young persons suffering sever disc degeneration, there is a correspondingly severe damage to the zygapophyseal joints .As stated by Mooney in his Presidential Address for the International Society for the Study of the Lumbar Spine " the human intervertebral disc lives because of movement".
It is axiomatic to state that the IVD undergoes degenerative changes which can lead to clinical symptomatology [98,99]. He nature of the degenerative process, however, and the specific etiologies of disc degenerations are far from being understood. Biochemical analysis of degenerated IVD's indicate that at least some of the changes resemble those seen in aging discs which are considered normal, or non-degenerate [92, 100]. Further, discectomy is followed by changes in the chemical composition of the disc which resemble human degenerated discs[87, 88]. Mitchell et al. point out that there is a divergence in the metabolism at some point in time at which point the disc may be identified as being degenerate, in contrast to normal changes due to maturation of the convective tissue with age. None of the studies, however, address the specific etiology of disc degeneration and herniation. What, for example, are the subclinical changes occurring in the components of the disc and motor unit that precede and set the stage for frank herniation or degeneration? It is widely recognized that the early changes in disc degeneration are clinically imperceptible.
As described by Parke, the IVD is a fibrocartilagenous complex that connects two adjacent vertebral bodies. Biochemically and physiologically, the disc appear to be specialized forms of cartilage. Each disc consists of three distinguishable components[63, 102], the annulus fibrosus, the nucleus pulposus and the cartilaginous end plate. It may be considered, however, that the transition zone between nucleus and annulus represents a distinctly different area of the disc[63, 103]. Since the three components of the IVD differ dramatically in their composition, organization and function, each will be discussed separately.
The Nucleus Pulposus:
It is now recognized that there is a significant number of cells distributed through the nucleus pulposus,and the number increases with the age of the individual [102, 104]. Cell types represent a mixture of chondrocytes and tissues macrophages , and both are believed to be active in the turn over of the extracellular matrix throughout life . The metabolism of the nucleus is relatively brisk [102, 105], and there is apparently a significant turnover of both proteoglycan [29, 103, 105] and collagen components . The collagen of the nucleus is qualitatively different from that of the annulus, consisting exclusively of Type II collagen . This changes gradually to Type I collagen on going from the nucleus to the outer annular fibers [`02, 106]. In the nucleus the extracellular matrix resembles that of cartilage, consisting of a loose fibrous mesh of collagen fibers whose interstices are interwoven with extremely large strands of proteoglycan molecules [46, 101].
The collagen and proteoglycan, together with the ions and water drawn into the substance of the matrix, form a biological gel . In perhaps no other tissue is the hydrophilic nature of proteoglycans more significantly demonstrated than in the nucleus. It is the proteoglycans and the water they imbibe into the disc that account for the unique hydraulic and hydrodynamic properties of the nucleus [85, 102]. Proteoglycans thus account for the elasticity in the biological spring function of the nucleus. The amount of water in normal adult nucleus pulposus is about 81%, but ranges from as much as 92%  at birth to 70% in later years [102, 108, 109]. The water content of the annulus, on the other hand ranges from about 78% at birth to 70% in later years, with the normal adult annulus consisting of about 73% water [108, 109]. It is known that the pressure, and therefore the water content, increases with age to a maximum during the fourth decade, then decreases progressively thereafter .
The pressure within the disc varies too with position and weight of the individual. In a 70kg male, the load in kg on the third lumbar disc ranged from a minimum of 20 in a reclining, relaxed position, to 100 standing erect, 142 sitting upright, 150 with the trunk bent at 20 degrees, 215 with 20 degrees flexion when lifting a 10 pound weight in each hand . Great enough pressures are commonly believed to cause ruptures of the IVD, leading to impingement on the nerve roots which course behind them on their way to the periphery. Careful studies reveal, however, that bulging and rupture of the annular fibers occurs only after degeneration of the nucleus has progressed substantially . After age 40, virtually all spines show signs of nuclear degeneration. There is a progressive decrease in proteoglycan [89, 92] accompanied by a loss of water from the nucleus . There are also qualitative changes in the proteoglycans with age and degeneration. The proteoglycan monomers are of larger size , and their ability to associate with hyaluronate to form large aggregates is diminished [2, 9, 90] with age. There is also a change in composition with increasing proportions of keratin sulfate, compared to chondroitin sulfate [90, 104, 105].
Degenerative changes of the nucleus after ventral herniation are described by Lipson and Muir . There is an almost complete loss of the nucleus at the time of incision, and by two days there is no nuclear material identifiable. In the material remaining, there is an initial decrease in water and proteoglycan content, followed by a rapid increase in the content of these components to a peak about five days after herniation, and then declining continuously thereafter to a minimum about four months after herniation. After one week, the border between the nucleus and annulus was unidentifiable, and by two weeks the ventral annular lamellae had become disorganized. Within the first month, the area of the nucleus had undergone fibrous proliferation, until the space was filled with fibrous tissue.
The Annulus Fibrosus:
The annulus fibrosus consists of layers, or lamellae, of collagen whose fibers are aligned and oriented at an angle of 60–65 degrees from the vertical axis . Alternating lamellae have their fibers angled on alternate sides of the vertical axis, so that the angle formed between the fibers of adjacent layers is 120–130 degrees. There is no distinct demarcation between the nucleus and the annulus, the two blending into one another like two extremes of a continuum . The region of contact of the nucleus and the annulus is referred to as the transition zone , and is characterized by fibrocartilage , ill defined lamellae and high metabolic activity . The lamellae are composed of Types I & II collagen, the former of which is found in increasing proportion as one progresses radially from the nucleus [102, 106]. It is considered that this difference helps to account for the fact that the outer lamellae of the annulus are more fibrous and highly ordered and have a higher tensile strength, whereas the lamellae which are closer to the nucleus are more disorganized, less well defined and more compliant. The more peripheral lemellae are anchored into the bony rim of the vertebral body, and the more central lamellae are anchored into the vertebral end plate [40, 85]. Lamellae are thicker anteriorly, thinner dorsally.
The annulus is intimately involved in disc herniation, because it is a failure in the annular fibers, resulting in splitting of the annulus, that allows extrusion of the nucleus pulposus when a disc herniates . The etiology of this process, however, is far from understood . Popular belief holds that rupture or protrusion of an IVD is due to excessive pressure from within the disc generated by the nucleus pulposus. Roaf  has shown, however, that excessive compressive loads on the vertebral motor unit leads to a blow-out of the vertebral end plate, never of the annular fibers.
The annulus is considered to be a pressure vessel which contains a hydraulic fluid, the nucleus pulposus [111, 115]. Deflation of the nucleus is associated with bulging of the annulus, in much the same way that loss of air in a pneumatic tire results in bulging of the tire . In fact, in all cases of annular tears, there is evidence of advanced degeneration of the nucleus pulposus [98, 100]. But it is not clear whether the annulus fails first, allowing protrusion, or ultimately extrusion of the nucleus, or whether the nucleus is the culprit, eroding away at the annular fibers. It has been shown that pressure distribution within the disc varies as a function of the state of degeneration of the disc. In the normal disc, annular bulging occurs only after changes in the nucleus, either loss of interstitial fluid or by bulging of the end plates . Younger, more hydrated discs appear to transmit compressive forces axially, into the end plate, whereas a more degenerated nucleus transmits forces more radially into the annulus . The result in this alteration of force distribution is tearing of the annulus, general collapse of the vertebrae, or marginal plateau fractures. 
Biomechanically, the aging and degenerate annulus show a marked decrease in GAG content, with a shift in the proportion of chondroitin sulfate and keratin sulfate . There is also a tendency for the proteoglycan monomers to form fewer aggregates with hyaluronic acid, in spite of the presence of abundant quantities of hyaluronate within the matrix. The collagen increases in collagen content as one examines discs down the spine . The proportion of types I and II collagen, however, does not change with age . The collagen also appears to become more fibrous and stiff . In experimental disc degeneration caused by ventral herniation , histological changes reflect proliferation of chondrocytes which undergo metaplasia to fibrocytes. Newly formed collagen is laid down in a erratic "haystack" pattern, leading to the formation of scar tissue. Proteoglycan content decreases in the annulus with age, [91, 106], but in contrast to the nucleus, the proportion of keratin sulfate to chondroitin sulfate actually decreases .
The Cartilaginous End Plate:
The cartilaginous end plate (CEP] is an integral part of the disc, and plays a strategic role in the dynamics of disc development and function . Because the disc is a vascular and isolated from other body fluid compartments , nutrients enter and waste leaves the disc through the highly porous, cribriform cartilaginous end plates. Its structure and function differ from that of cartilage covering the articular surfaces of the zygapophyseal joints which are dense, weight-bearing, gliding surfaces. Unlike the articular cartilage of the diarthroidial synovial facets, there is no dense plate of compact osseous mineral separating the end plate cartilage from the spongiosa bone of the vertebral bodies beneath . This is apparently essential for the exchange of nutrients between the vascular beds of the subchondral spongiosa bone and the disc material, but creates a particularly precarious physiological situation . It also follows from this arrangement that changes in the subchondral bone affect the exchange of nutrients and waste between the disc and bone .
The end plates are flexible, and are the primary structures which undergo deformation when a motor unit is compressed . They have been shown to bulge into the vertebral bodies under compressive loads, and in the normal disc, it is the CEP which first ruptures under excessive compressive loads . This leads to the common radiological finding of Schmorl's nodes . The end plates participate in the dynamics of the disc also by allowing the bulk flow of water out of the nucleus under compressive loading . It is well known that the degenerate disc exhibits different mechanical characteristics than the normal discs , and the cause is commonly ascribed to the changes occurring in the nucleus pulposus . Theoretical considerations, however, do not distinguish between a softening of the annulus and an increase in the rigidity of the end plate [60, 118]. It is believed by many authors that degeneration of the CEP precedes degenerative changes in the nucleus , but the issue is far from resolved.
The meninges are mentioned here for several reasons: foremost, they are connective tissue in nature and they are intimately associated with the vertebral motor unit . Within the intervertebral foramen (IVF), the dura is known to form strong adhesions to the pedicles of the foramen, as well as to the posterior longitudinal ligament and the facet joint capsule . The dura and its associated arachnoid layer are indented and drawn into the IVF at each segmental level, lining the opening to minimize mechanical irritation to the nerve roots and with the dorsal root ganglion , investing then to become the root sleeves as the roots pass through the IVF.
Clinically, root sleeves fibrosis or dural hyperplasia leading to nerve root stenosis and fibrous adhesions of root sleeves to the pedicles of the vertebrae are well documented and are known to be involved in clinical symptomatology . In the region where the meninges join the nerve roots large cysts are known to develop and extend into the dorsal root ganglia (DRG), often occluding significant volumes of the ganglia . On gross examination they can often be seen bulging beneath the root sleeves which cover the roots. Although the cysts are often asymptomatic and seen only incidentally in myelography, they have been shown in some cases to give rise to clinical symptoms [67, 124].
The causes are unknown, but chronic irritation or inflammation have been implicated . Recent investigations suggest that dural "ligaments" which fix the nerve roots to the ligamentous and osseous structures of the IVF might be involved in the etiology of sciatica . Given the connective tissue nature of the meninges one might expect similar changes in them following immobilization as are seen in all other forms of connective tissue. Whether or not these processes are caused or affected by immobilization or restriction of vertebral motion remains to be evaluated, and would be a significant factor in testing the hypothesis set forth in this paper.
The existence of widely divergent and apparently conflicting ideas concerning chiropractic theory and practice is evidence of the extreme complexity of the topic and points to the need for a greatly expanded research effort to elucidate the underlying mechanisms for effective chiropractic treatment. Chiropractors throughout the world are grappling with this dilemma on a daily basis, each approaching it with different theoretical and methodological approaches. Advances in this area of research are evidenced by the work of Sato and Swenson  who demonstrated that spinal manipulation evokes visceral sympathetic reflex responses which alter physiological functions of the whole animal.
Vernon et al. have shown in humans a significant increase in plasma beta-endorphin levels after cervical manipulations . Such research supports a rationale for the use of spinal manipulative therapy to evoke general, and perhaps specific, physiological responses, and suggests a physiological basis for the effectiveness of chiropractic adjustments in the care and treatment of a wide variety of systemic conditions. Progress is hampered, however, by lack of experimental models and laboratory facilities to test realistic biological hypotheses .
It is my hope that this paper will contribute in some small way to the development of a more substantial theory of chiropractic by presenting a coordinated concept of a component of chiropractic subluxations referred to here as fixations. In the most restricted sense of the term, fixation refers to the immobilization of a joint by any on of a number of mechanisms, be it muscle spasm, splinting, ankylosis, trauma, etc.
In its broader sense, it can refer to a restriction in movement, within a normal range of motion. It has been demonstrated that complete immobilization is not essential for degeneration to occur [4, 39], and conversely that degeneration can occur following loading within normal physiological ranges . By whatever criteria used to describe the phenomenon, fixations are almost universally recognized as components of subluxations. I have coined the term "immobilization degeneration," a term used throughout this article, to refer to the degenerative changes in an articulation which can be ascribed exclusively to immobilization, as distinguished from trauma, abnormal load-bearing or structural variation.
The term 'subluxation' from a medical standpoint means simply an incomplete or partial dislocation . From a chiropractic standpoint, however, the term represents one of the foundation principles of the art and practice of chiropractic. The International Chiropractors Association has adopted the following definition of subluxation :
"Any alteration of the bio-mechanical and physiological dynamics of the contiguous spinal structures which can cause neuronal disturbances."
The American Chiropractic Association definition sounds surprisingly similar:
"An aberrant relationship between two adjacent structures that may have functional or pathological sequelae, causing an alteration in the biomechanical an/or neuro-physiological reflections of these articular structures, their proximal structures, and/or other body systems that may be directly or indirectly affected by them ."
Subluxation would thus be categorized medically as an arthrosis , a physiological imbalance, a joint failure, in which mechanical factors play a role. The criterion of neurological involvement is a point of contention for many both inside and outside the profession. Yet, the clinical experience appears to support such a concept; most obviously in the ability of chiropractic to reduce the pain in low-back syndrome and sciatica . More subtle manifestations of this phenomenon continue to strike heated controversy, again from within and without the profession.
A more thorough presentation of the neuropathophysiological component of subluxations was reviewed recently by Dishman , who refers to the Chiropractic Subluxation Complex (CSC), a concept which he attributes to Dr. John Faye. Others prefer the term "vertebral subluxation complex" (VSC), a term which will be used throughout this discussion. The VSC is stated to consist of five generalized components : 1) kinesiopathology, 2) neuropathology, 3) myopathology, 4) histopathology, and 5) biochemical abnormalities. While this selection of headings generally encompasses most of the acknowledged aspects is in need of a more refined development.
According to chiropractic theory, alteration of the biomechanical and physiological dynamics of contiguous spinal structures is responsible for the appearance of symptoms resembling serious pathological conditions. It is usually presumed that the mediating factor in this more generalized or systemic response to spinal articular degeneration is the nervous system, so that most theories of subluxation involve a neurological component. This is particularly significant in light of the segmental nature of the nerves emerging from the spine, and the integral association of the segmental nerves with the spinal articulations.
Clinically, nerve root compression and radiculitis have been described as giving rise to a spectrum of clinical symptoms  including otological manifestations , respiratory problems simulating cardiac asthma , spastic paraplegia , claudication , renal pain , chest pain simulating coronary occlusion , and sexual impotence .
Subluxations are believed by many chiropractors to actually cause or precipitate degeneration in remote areas of the body, such as the stomach, lungs or heart . The clinical implications of this are significant. If a patient only appears to have a serious condition, such as coronary occlusion, and these symptoms are due to the presence of a spinal subluxation which can be relieved by a chiropractic adjustment, the need for intensive therapy is obviated. If, on the other hand, the patient actually does have a serious condition of this type, the management program would differ markedly. In light of this rationale, which is fundamental to the thought processes of the chiropractic practitioner, it is important to note the experimental findings of Sato and Swenson . These investigators showed that upon movement of a spinal motion segment, they could measure a specific response pattern through the sympathetic nerves which supplied the adrenal gland, a pattern which differed from that measured simultaneously to the kidneys. This study extended the observations of Sato of similar effects of peripheral cutaneous stimulation on adrenal activity [137, 138] and gastric motility  as well as the effect of peripheral joint motion on cardiac activity . The more specific relevance of these finings to chiropractic theory is as yet to be determined, but the mere observation of such a phenomenon related to vertebral motion is of fundamental significance to chiropractic theory.
Mechanisms of intervertebral joint fixation were recently reviewed by Rhalmann . It is trivial to state that joints are designed for motion, and spinal articulations are no different in this respect that other joints. In the preceding pages specific, demonstrable changes which occur in connective tissue as a sequel to immobilization have been documented. All types of connective tissue are involved, and each reveals its own unique pattern of histopathology. Degenerative progression is associated with alteration or loss of joint function, thus providing the basis for the kinesiopathological component of the VSC. It is proposed here that the degenerative changes following immobilization of spinal articulations are fundamental to the VSC, and represent a reasonable conceptual basis for the design of experimental models to study the effects of manual therapies, and particularly the chiropractic adjustive procedures, on the course of degeneration. The advantages of such a model include the incorporation of specific measurable parameters for evaluating the effects of chiropractic adjustive procedures on the course of degeneration. Such parameters include chemical and histological analysis of inflammatory activity, evaluation of physical characteristics of connective tissue, such as resistance to sheer stress and tissue compliance, compositional changes in proteoglycans, and chemical analysis of changes in collagen cross-linkages upon immobilization and following adjustments.
Of particular interest to chiropractic theory is that the degenerative changes seen in immobilized joints appear to reversible on subsequent remobilization [4, 141]. Palmoski et al.  showed that the biochemical changes in articular cartilage following immobilization were reversible upon remobilization of the articulation, thus supporting the observations of Evans et al.  who showed that the gross pathological lesions associated with degeneration following immobilization were, to some extent, reversible upon remobilization of the involved joint.
It is not clear whether the same is true of degenerative joint disease. In studies on immobilization-induced osteoarthritis in rabbit knees  it was shown that distraction of immobilized joints inhibited the development of osteoarthritis. It is reasonable to expect that distraction of immobilized joints inhibited the development of osteoarthritis. It is reasonable to expect that the same would be true of the spinal zygapophyseal articulations. The prediction from this is that chiropractic correction of spinal fixations (local immobilizations or restricted ranges of motion) might be of benefit in some forms of osteoarthritis. Further support for this premise is the widespread use of continuous passive movement to promote healing in ligaments immediately post surgically  and throughout recovery.
Short-term immobilization is said to be entirely reversible , although it is not specified exactly how short a time is implied, nor in what species. Obviously, a short time in humans could be a substantial period of the life span of a rat. After 40 days of immobilization, rabbit knees showed a return to normal function but metabolism within the joint capsule did not return to pre-immobilizatio levels . In the final analysis, the duration of immobilization definitely influences the final range of motion attained upon remobilization . In rabbits whose knees were immobilized for 110 days, complete restoration was only seen after extended period (200 days) of remobilization . There appears to be a threshold beyond which degeneration becomes irreversible , but its parameters have yet to be delineated either in animal models or in humans .
Inherent in the idea of subluxations is the idea that degeneration of one area of the body, i.e. spinal articulations, leads to the degeneration of other body areas remote from the site of initial degeneration. The effects of these processes on visceral function have been thoroughly reviewed by Dishman . What is clear at this point is that degeneration of one joint leads to degeneration of other joints remote from the site of the primary lesion. Peacock  points out that often the more disabling loss of motion due to joint stiffness is in a joint which is distant from an injured or infected joint. Akeson et al.  state that patients with a Colle's fracture often are permanently handicapped by restriction of shoulder and finger motion secondary to treatment of the wrist fracture. Experimentally it has been shown that immobilization of the knee results in degeneration of the hip joint as well as the knee [4, 38] . In studies on the spine, it has been shown that lesions in one area of the spine lead to structural and functional alterations in other parts of the spine , the effect being greatest in discs immediately adjacent to fused joints. It has also been noted that degenerative discs often occur in areas adjacent to previously degenerated discs, but the correlation depends greatly upon the vertebral level considered , with a strong association above L3, but not at L4 and L5.
An important consideration in the use of immobilization degeneration as a model of subluxations is its use as an experimental model for research into the etiology and pathogenesis of osteoarthritis. Maroudas  discusses a self-perpetuating destructive process which follows joint immobilization, and which involves successively deeper layers of cartilage. This was supported by the work of Kempson et al.  who suggest that once any disruption in the collagen mesh occurs, the consequences would be progressive. The progressiveness of such lesions points to a need to regularly maintain the mobility of all spinal (and extremity) articulations, even in cases of degenerative disc disease or scoliosis. The issue is stated succinctly by Taylor et al ; "a sacrifice of spinal mobility is not a final acceptable solution to (scoliosis)." Immobilization can exacerbate pre-existing connective tissue trauma and the trend in orthopedics is toward shorter periods of immobilization and structured exercises to rejuvenate damaged connective tissue [13, 145].
While immobilization is a useful tool in studying some of the changes occurring in OA, there are significant differences between the two processes. In humans immobilized for prolonged periods of time by paralysis or other means, contracture and fibrous ankylosis occur, rather than osteoarthritis . It is further believed that degenerative arthritis can occur in joints which have not been immobilized or subjected to any recognizable trauma , but clinically this is difficult to establish. Initiation of OA is characterized by focal changes in articular cartilage  rather than more generalized tissue involvement. Moskowitz  describes the early changes in human OA as loss of surface continuity, fibrillation, vascular proliferation and osseous hyperplasia. Thaxter  points out, however that these changes were rarely observed in their experimental work on joint degeneration following immobilization.
It is now generally agreed among rheumatologists that the events leading to the initiation of osteoarthritic degeneration are different from those processes which support further degeneration [23, 86]. According to Maroudas  in osteoarthritic cartilage there is a disruption of collagen fibers, thereby relaxing the elastic constraints of the collagen network on the hydrated gel matrix of proteoglycan and water. Thus, in degenerated cartilage, even though there is a decrease in proteoglycan, there is an increase in water content leading to a swelling and softening of the cartilaginous matrix [17, 35, 37]. Although in immobilization degeneration there is also a loss of PG and an increase in water content, there is a thinning of the cartilage without a disruption of the basic matrix structure .
In immobilized canine knee cartilage there is a defect in the aggregation of proteoglycans leading to an increased concentration of smaller aggregates of proteoglycans within the tissue . Observations on gross histological specimens of human knee cartilage suggest a similar pattern of degeneration in humans following immobilization . These observations suggest that the initial degenerative changes in the articular cartilage following immobilization are related to proteoglycan loss rather than to collagen degeneration. Similar conclusions were drawn concerning other connective tissue components in immobilized knees  and in degenerated discs .
In the medial collateral ligament of rat knees, loss of proteoglycan is accompanied by a significant decrease in ligament volume . There is no detectable change in the content of collagen periarticular connective tissue at any point in the degeneration processes of immobilization  or in articular cartilage of joints affected by osteoarthritis , although there are changes in its composition and organization . There is an increase in the diameter of collagen fibers following immobilization  , suggesting an increase aggregation of individual collagen fibrils . In the menisci of human osteoarthritic knees, there was a decrease in collagen in degenerate areas, but non-collagenous protein and hexosamine were increase  . Woo et. al  failed to demonstrate collagen accumulation or increase rate of collagen synthesis in combined periarticular connective tissue of rabbit knees immobilized in flexion.
In other studies  little change was observed in the distribution of collagen in normal vs degenerated discs, but water and proteoglycan content decrease, especially in the nucleus. The observations on water proteoglycan content decreased, especially in the nucleus. the observations on water and PG in the nucleus were confirmed by Pearce & Grimmer  but these investigators noted an increase in collagen in degenerated discs.
In discussing proteoglycan deficiencies of aging human articular cartilage, Poole  states that "In view of the known importance of PG in maintaining the compressive stiffness of articular cartilage, we would expect that these deficiencies may in the long term be deleterious to the well being of human cartilage." It is known that PGs play an essential role in regulating the mechanical properties of the IVD , tendons  and ligaments [47, 48]. It is not just the quantity, but also the quality of PG that affects the physical state of connective tissue. Although a complete discussion of these components is beyond the scope of this text, it is important to mention a few major details of these important macromolecules.
The three major GAGs of PGs are chondroitin-4-sulfate, chondroitin-6-sulfate and keratin sulfate [49, 149]. The relative proportions of the above GAG components are known to exert an influence over the fibrillar organizational pattern of collagen . Higher proportions of keratin are seen in ligaments and tendons associated with Type I collage, whereas chondroitin is the predominant GAG in articular cartilage and the nucleus pulposus where Type II collage predominates . It is has been further shown that the proportions change following immobilization or other stimuli which lead to degenerative or plastic changes in connective [63, 90, 100]. PGs are believed to play an active roll in determining the size and organization of collagen fibers in tissues [46, 150, 151]. This is particularly significant in light of the change in collagen fiber diameter noted in medial collateral ligaments following immobilization .
In both normal and prolapsing discs the products of mucopolysaccharide breakdown appear to participate in the metabolism of collagen . With regard to the development of scoliosis, alteration of PG/collagen ration could reduce the normal turgidity of young NP with loss of intrinsic stability of the spine to account for the rapid increase in curves during growth spurts . A Proteoglycan aggregation defect has been described in immobilization degeneration which is detectable within the first week of immobilization  , and a similar defect has been reported in experimental disc herniation , but it is not clear whether this is the cause or result of degeneration. Other authors  also emphasize the similarities of disc degeneration following ventral incision, and the changes seen in degenerative disc disease. The degenerate nucleus, because o f its decreased proteoglycan content and increased fibrotic nature would no longer behave hydrostatically .
One of the complicating variables in studies of immobilization is the position in which the joint is immobilized. Immobilization of rabbit knees in extension produces changes similar to those seen in OA , while a significantly different pattern of degeneration is seen in joints immobilized in flexion [12, 15, 47]. It is likely that the difference is related to weight bearing, since opposite changes are seen in the same cartilage in samples taken from weight-bearing vs non-weight bearing areas . Although connective tissue changes resulting from immobilization per se differ from those seen with changes in load-bearing , it is often difficult to separate their individual contributions.
In immobilization in extension, for example, the effect is to create a continuous load-bearing on the articular cartilage . Thaxter et al  feel that muscle contraction causing a static compression of the articular cartilage probably contributes to the degenerative changes occurring in immobilized joints. In osteoarthritis there is an increase in the total hexosamine content (GAG) in degenerative areas of the menisci  . Similar results are seen when rabbit knee joints are immobilized in extension , but the opposite is seen, i.e. a decrease in GAG content, in rabbit knees immobilized in flexion . According to Videman et al  the discrepancy between immobilization in flexion versus that in extension may be due to the presence of differently oriented forces and stress in the joint structures in the two different positions. While the real reasons for the osteoarthritic changes in joints following immobilization are mostly unknown , they are believed to be related to the effect that continuous compression has on chondrocytic activity.
Immobilization may disturb chondrocyte function and depress GAG synthesis until degradation of cartilage matrix provides a stronger stimulus leading to increased GAG production by the cells.  The most widely held mechanism for this is an interference with exchange of nutrients and waste between chondrocytes of cartilage and the synovial fluid [147, 154]. An increasingly popular view is that mechanical stress exerts an affect directly on chondrocytes . In this model, proteoglycans and collagen, as well as other molecular components of the matrix, such as fibronectin , play a primary role in transducing mechanical energy into biochemical and morphological expression in tissue cells [49, 156, 157, 158]. Akeson et al  have shown that in immobilized fibrous tissue, such as ligaments and tendons the earliest measurable change is a decrease in proteoglycans and water content. It appears, however, that the result of such loss is ligamentous laxity. There is an approximately 60% decrease in the stiffness of medial collateral ligaments of rats  and rabbits  after immobilization in flexion for 40 and 63 days, respectively. Similar changes were observed in the anterior cruciate ligaments [57, 58] and are proposed to occur in paraspinal ligaments during degenerative processes .
The response of paraspinal ligaments needs to be investigated more thoroughly, since other investigators propose that in scoliosis, the paravertebral ligaments, tendons and joint capsules on the concave side of the curve resist restorative forces, both internal and applied . The articular capsule is known to thicken and shorten when a joint is immobilized in extension, [5, 38], and this is accompanied by an increase in proteoglycan content and synthesis . When immobilized in flexion, however, there is a decrease in net proteoglycan synthesis, and the capsule decreases in thickness [12, 38] and shows definite evidence of contracture . The capsule also thickens in osteoarthritic joints [5, 16]. In studies on joint stiffness following immobilization it was clearly demonstrated that capsule contracture contributed significantly to the observed stiffness . After four weeks immobilization half of the group of rabbits studied had complete limitation of motion in the immobilized position, the other half having partial limitation. The contracture could be released by muscle section only in the animals with partial restriction.
Cutting of the capsule was required to release restricted movement in all other animals . It thus appears that different components of a joint contribute to stiffness at different times following immobilization. In the end state, of course, restriction is due to bony ankylosis . The effect of muscle atrophy is significant in this regard. After immobilization of the rabbit knee in flexion, progressive muscle atrophy was observed for the first ten days to two weeks ; subsequently there was some restoration of muscle bulk . When the limbs were examined after sacrificing the animals, it was observed that with muscles intact, the knees were restricted to 30 degrees of extension, but with excision of the muscles, the joint could be extended freely to 150 or 160 degrees.
Thaxter et al.  propose that static compression of articular cartilage resulting from muscle contraction contributes to the degeneration of articular cartilage in immobilized joints. In the spine, on the other hand, where the proportion of muscle shortening and extent of osseous excursion during movement are far less than with in the extremities, muscle atrophy may play a less significant role.
The one factor which is almost universally recognized as contributing to connective tissue degeneration in immobilized or otherwise altered joints is a change in the pattern of forces transmitted through the joint . Further, the manner in which the force in delivered, not just the magnitude of the force, may b;e significant in determining the response of the tissue . It is possible to induce osteoarthritis in rabbit knees simply by exposing them to repetitive impulsive loading within physiological ranges, the underlying cause of such degeneration being a failure of the musculoskeletal system to properly attenuate peak dynamic forces encountered during regular activities. Since the tissues of joints are capable of sustaining minimal amounts of damage without progressive change, it is hypothesized that repetitive cumulative microdamage leads to bony remodeling, stiffening, and progression of cartilage lesions . In studies on bipedal mice it was concluded that continuous stress on the IVD from abnormal posture resulted in accelerated disc degeneration which subsequently developed into disc herniation , and these authors propose that a change in stress applied to the vertebral column is one of the main factors that induce disc degeneration.
It is important to repeat here that the response of each tissue to altered mechanical stress is unique. For instance, the IVD can withstand considerable abnormal physical stresses, whereas articular cartilage appears particularly sensitive to abnormal mechanical stresses . It is generally acknowledged that a certain amount of mechanical stimulation is essential to the normal function and integrity of a joint ., and either excessive or decreased stress patterns lead to a change in the metabolism of cells of the tissue involved . Some portion of this process appears to be inherent in the response patterns programmed into the tissue cells and probably represents a normal physiological response to stress [49, 160]. Clearly, however, at some point there is a divergence from the normal plastic response to what is considered a degenerative state of the tissue , and mechanical forces play a significant, if not primary role in this process . It is generally agreed that abnormal mechanical conditions predispose to degenerative changes in the misloaded joint , and it has been postulated that most cartilage destruction could proceed mechanically . Depletion of proteoglycan or degradation of collagen can accelerate mechanical damage to articular cartilage .
The mechanical properties of connective tissues thus depend upon those of their major components, collagen and proteoglycans, as well as on their interaction . It as clear that mechanical failure of the IVD could result from local variations in chemical composition . One major question related to chiropractic theory is whether immobilization of a vertebral motor unit can, independently of other changes in the IVD, lead to disc degeneration. Studies on biochemical changes in the IVD of patients with adolescent idiopathic scoliosis indicate that the effect is very strongly dependent on the age of the individual when stress is applied [63, 64]. In humans after the second decade there is a metamorphosis in the disc which leaves is less pliable , and in rabbits  and dogs  there are differences in proteoglycan metabolism in normal mature fibrocartilage of the IVD compared to immature animals.
The information pertaining to connective tissue changes following immobilization presented in the main section of this paper supports the idea that immobilization due to trauma or other causes could lead to local biochemical changes in the IVD resulting in a loss of the mechanical strength of the disc. This idea is consistent with the known pathogenesis of disc degeneration, in which changes begin in the transition zone between the nucleus and annulus [17, 64], the area where there is the greatest degree of metabolic activity [63, 103]. This is also supported by research on scoliosis  which shows that there are differences in the biochemical composition of the concave and convex sides of the same disc, with the differences greater at the apex of the curve than elsewhere. The concave side shows an increase in chondroitin sulfate, with no change in either keratin sulfate or hyaluronic acid; the convex side shows a decrease in chondroitin sulfate with an increase in both keratin sulfate and hyaluronic acid.
Collagen levels, too, were generally lower on the concave side and total proteoglycan was decreased in the nucleus pulposus , both effects maximal at the apex with differences diminishing caudally and cranially . These changes are considered to be secondary to development of the abnormal curve and not causal factors in scoliosis, but they point to the effect of asymmetrical mechanical forces on the biochemistry of the annular forces on the biochemistry of the annular fibers of th IVD . Further, the type of matrix produced in the disc depends upon the nature and duration of the mechanical forces involved . In studies of the rabbit flexor tendon  it was shown that pressure bearing areas of the tendon had a more fibrous pattern of organization in the areas exposed to high tensional stresses. Immobilization of a joint is capable of precipitating a form of arthritis which might well be mistaken in its later stages for osteoarthritis [6, 7, 8]. Although osteoarthritis is generally believed to be a non-inflammatory process, inflammation is seen in about 75% of histologically sampled osteoarthritic joints , and in another group, about 20% of joints undergoing surgery for OA showed evidence of moderate, focal, chronic synovitis . It is well known that fragments of all of the major connective tissue components are involved in some aspect or phase of the inflammatory response and wound repair . Inflammatory responses to collagen are well known in relation to rheumatoid arthritis , and a cellular immunity to cartilage proteoglycan has been identified in polychondritis , with a striking absence of humoral (antibody) immunity. Fragments of hyaluronic acid are angiogenic , that is they stimulate the development of capillary beds which invade areas of chronic infection or degeneration to bring adequate supplies of blood-borne defense mechanisms to resolve the problem.
It is likely that the inflammatory response contributes to the neurological manifestations of subluxations. The release of small and moderately sized inflammatory mediators into the venous plexus of the spinal column (venous plexus of Bateson)  might access sensitive neurological elements in or around the intervertebral foramen. A similar mechanism, referred to as 'Chemical Radiculitis,' was put forth to explain low back pain resulting from intervertebral disc prolapse involving the spinal nerve roots . The basic idea is suggested here as a possible mechanism whereby the degenerative process of spinal articulations might involve the neurological structures of the IVF. I have proposed elsewhere  that the Dorsal Root Ganglia (DRG) are the most likely sites of neurological involvement in the chiropractic spinal subluxation, due to their unique physiological characteristics and location within the intervertebral foramen. Particularly, the DRG are believed to be lacking or markedly deficient in a blood-nerve barrier . Further, they are drained by the same venous plexus that drains adjacent spinal structures, such as the osseous trabeculae of the subchondral bone of the articular pillars, the hyaline end plates of the IVD and the synovial capsule . It is likely, therefore, that inflammation of the soft connective tissue elements of the spine could release chemical mediators into the venous blood that could set up an inflammatory response in the DRG . The effects of this reaction would involve all sensory modalities of the involved segmental nerve, leading to increased muscle tonus in response to increased proprioceptive input and a heightened perception of pain due to a sensitization of the nociceptors to otherwise normal stimuli .
The time course of events in immobilization degeneration is a significant consideration in light of the proposed model. Within one day, there are measurable changes in chondrocyte activity, described as an increase in colloidal iron staining of the chondrocytes, followed on the second day by a noticeable loss of metachromasia in the superficial and transitional zones of cartilage, indicating loss of proteoglycan . This corresponds with the time observed in the IVD for changes to occur in the pericellular matrix in response to the injection of radiolabled sulfate . Extrapolation from this study suggests that changes following immobilization begin almost immediately. Ultrastructural changes can be seen by electron microscopy after 3 days immobilization in rabbits , the earliest time period studied by this method. By the fourth day, all chondrocytes were either pyknotic or had completely disappeared, and by day six, in rat knees, there is an almost complete loss of metachromatic staining with a corresponding loss of colloidal iron staining of the chondrocytes . In canine knee cartilage, a proteoglycan aggregation defect was shown to develop by 6 days immobilization . In ligaments, the effect is equally as rapid ; 35S-sulfate uptake in medial collateral ligament doubled within 4 days, and quadrupled within 1 month following immobilization.
The articular capsule can be seen to have thickened after 10 days in both knee and hip joint of rabbits whose knees were immobilized in extension . Osteophyte formation can also be discerned within 10 days of immobilization of rabbit knees . In rats, gross structural changes can be seen in apposed articular cartilage by 15 days immobilization , at which time there were also signs that the synovial fluid was being replaced by fibrofatty connective tissue which formed adhesions to the articular cartilage [4, 39]; the articular cartilage was lusterless, but showed no observable lesions . Within 45 days there is ulcerative erosion of the superficial layers of cartilage in rat knees, and by 60 days the lesions involved the subchondral bone . Similar changes were seen in rabbits whose knees were immobilized in moderate [15–20] flexion ; the articular surface was covered with a synovial pannus, the cartilage had lost its luster and color, and small vertical fissures appeared at the junction between areas of apposed and unapposed cartilage.
Studies on articular cartilage from humans in extremities which have not been utilized indicate that pathological changes follow a similar pattern as described above . In one of the few publications on immobilization of the human spine, Baker et al.  found fibrotic degeneration of the articular cartilage and bony fusion within six months following fusion of the associated vertebral bodies for spinal tuberculosis. This supports not only the idea that observations on animals can be used to model these processes in humans, but that spinal articulations are sensitive the effects of immobilization.
The experimental results cited above are for the most part, obtained on extremities; knees, hips or elbows. In these areas, it is relatively straight forward to determine the position and the degree of immobilization in the involved joint . In the spine, however, the situation is vastly more complicated, since immobilization of a single articulation is much more difficult and an assessment of the effectiveness of the immobilization procedure and the localized consequences of immobilization all pose formidable problems. It appears, too, that the spine represents a system of articulations with unique physical, chemical and functional properties, differing from all other joints of the body . It is an interesting contrast in this regard to note that in degenerative disc disease, the fibrillary changes of the cartilaginous end plates cannot be distinguished histologically from the changes in diarthroidial osteoarthritis . In the final analysis, however, only research on spinal articulations can answer the fundamental questions regarding spinal degeneration.
Adding further to the uncertainty of applying experimental results to clinical situations is the use of a variety of experimental animals including rodents, rabbits, dogs and monkeys. Selection of animal models is critical, since two major types of vertebral morphogenesis are known, the chondrodystrophic types [63, 64]. Further, humans have vertebrae which are unique among animals , in that human vertebrae lack terminal epiphyses found in other animals. The difficulties of human experimentation in this regard are obvious. Nonetheless, human studies on osteoarthritis of the spine  and on changes in the vertebral motor unit following spinal fusion  support the tendency to extrapolate results from extremities to the spinal synovial articulations, and support using results from animal experiments to draw conclusions concerning human joint degeneration. Ultimately, however, results from animal experiments cannot be directly accepted for clinical practice .
Subclinical lesions are well recognized with regard to immobilization degeneration of articular cartilage . Muir  has pointed out that, at least according to medical diagnosis, osteoarthritis is asymptomatic in its initial stages, and is detectable only in later stages when radiological changes have developed. The medical attitude is appropriately encapsulated by the following quote from the resent medical literature : "Because there are so many different factors associated with osteoarthritis, one soon despairs of treating anything except the disease in its final stages with arthroplasty." The solution offered by these authors to this dilemma, in light of newly acquired information on the biochemical changes accompanying arthritic degeneration, is the chemical modification of the regeneration processes of the connective tissues to "alter the balance between degradation and repair."
The authors state that "the logical approach ... is to determine whether it is possible to block these processes by enzyme inhibitors simultaneously." The search for drugs to interfere with degenerative processes of osteoarthritis is supported by the work of Muir  in spite of her acknowledgment that the early period of development during which drug treatment would be most effective is clinically undiagnosable by current methods. While these authors acknowledge a primary role of mechanical stress upon the joint as a contributing cause of arthritis, manual therapy is not even considered as a viable alternative therapy program. Mooney , on the other hand, points out the dangers of inactivity and encourages mechanical therapy as the most rational approach to relief from degenerative disc disease. It is proposed here that the detection of articular fixations and their correction by chiropractic procedures can reverse articular degeneration and prevent the development of osteoarthrosis, and perhaps osteoarthritis as well. Certainly, in light of the acknowledged role of mechanical factors in the development of these conditions, something short of arthroplasty of the end stage disease or the complicated and dangerous aspects of drug side effects should be made available to the patient. Indeed, the molecular mechanisms which provide a rationale for chiropractic adjustive procedures are widely discussed in the literature. According to Naylor  changes in the connective tissue matrix, together with the effect of matrix components on the maturation of collagen are fundamental factors in the development of disc degeneration. From the material presented above, similar statements could be made about virtually every connective tissue component of a joint. Of particular significance is the permissive effect of loss of proteoglycans in allowing the formation of intermolecular bridges between collagen fibrils .
This is characterized by a decrease in the interaction between collagen and proteoglycans  Woo et al.  have proposed that intermolecular crosslinking interferes with joint extensibility by inhibiting free gliding of fibers in the nylon hose weave model of the connective tissue matrix. These investigators further state that forced motion of previously mobilized joints causes physical disruption of either the intermolecular crossbridging between collagen fibers of the adhesions between gross structures as demonstrated by Evans et al . It would appear, therefore, that the benefits of controlled forced mobilization as applied through chiropractic adjustive procedures are substantiated even at the molecular and metabolic levels of connective tissue structure and function.
It is of vital interest to chiropractic to test the theory of subluxations and evaluate the effectiveness of adjustive procedures using the models of immobilization degeneration presented in this paper. Of critical importance is the relationship of the neurological components to degenerative processes of the spine. Several specific questions to be addressed include:
The effect of short and long term immobilization on specific connective tissue elements of the spine. The most significant structures in this regard are the articular capsule, articular cartilage and the IVD, but include other dense connective tissue elements as well.
It would be important to evaluate the degree of immobility required to elicit degenerative changes in connective tissue of a joint. It is known that complete immobilization is not essential to induce degeneration, but limits of mobility representing a threshold level are not known.
The effect of inflammation of the articular and periarticular connective tissue on neurological components of the motion segment must be thoroughly evaluated. While attention is often focused on the nerve endings, it would be important to evaluate the effects of periforaminal inflammation on the segmental nerves, and particularly on the DRG.
The effect of ligamentous contracture on the threshold sensitivity of the joint proprioception requires careful study. Does connective tissue shrinkage increase the strain on embedded tissue receptors and place them in a state of increased or decreased responsiveness?
What is the effect of the high velocity,, low amplitude thrust of the chiropractic adjustment on the physical and chemical parameters of connective tissue reported in the literature? Does this procedure facilitate a re-establishment of normal tissue structure and function following trauma or immobilization?
Can adjustments diminish the severity of osteoarthritis, stop its progress, or prevent its development? The literature suggests that this is the case, but the critical tests have yet to be performed.
What is the effect of chiropractic adjustive procedures on the development of scoliosis? Can its progress be slowed or halted, and can it be prevented by regular chiropractic care? These are but a few of the significant questions which must be addressed in order to clarify the concept of chiropractic subluxations and to provide a rationale for chiropractic adjustive procedures.
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