6 - Molecular Genetics of Osteoarthritis

Authors: Moskowitz, Roland W.; Altman, Roy D.; Hochberg, Marc C.; Buckwalter, Joseph A.; GoldberG, Victor M.

Title: Osteoarthritis: Diagnosis and Medical/Surgical Management, 4th Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > I - Basic Considerations > 5 - Experimental Models of Osteoarthritis

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5

Experimental Models of Osteoarthritis

Margaret M. Smith

Christopher B. Little

Although the etiopathogenesis of osteoarthritis (OA) is still the subject of intense debate and research, its pathology is well established.1 The pathologic process of the OA joint is characterized by extensive fibrillation of articular cartilage in those regions subjected to high contact stress accompanied by sclerosis of subchondral bone. At the joint margins, osteophytosis and bone remodeling generally occur, the synovial capsule becomes fibrotic, and the lining is usually inflamed.2,3 As a consequence of the synovitis, the metabolism of type B lining cells, the synoviocytes, is disturbed, resulting in the biosynthesis of hyaluronan with a reduced molecular weight.4 Because the rheologic properties of hyaluronan depend on its molecular size and its concentration,5 a decrease in either leads to a decline of the viscoelastic and lubricating ability of synovial fluid, imposing additional mechanical stresses on articular cartilage and subchondral bone. There is also evidence that blood flow in the intraosseous vasculature of OA joints may be impaired owing to the presence of lipid emboli and fibrin thrombi.6,7 The ischemia so arising may compromise osteocyte viability, leading to necrosis and bone remodeling.6

The complex pathobiologic changes of human OA normally take several decades to develop and may be influenced by a multitude of factors, such as genetic predisposition, hormonal status, occupation, and body mass index, among others. The need to clarify the molecular events that occur in the various joint tissues at the onset and during the progression of OA has necessitated the use of models, which, although imperfect, can exhibit many of the pathologic features that characterize the human disease. In vitro studies using cell and tissue culture models have proven invaluable in defining specific molecular and cellular events in degradation of joint tissues such as cartilage. However, to fully understand the complex inter-relationship between the different disease mechanisms, joint tissues, and body systems, studying OA in animal models is necessary. The realization by workers in the field that OA is not a normal physiologic consequence of the aging process and that it might be amenable to therapeutic intervention provided a major stimulus to the development and use of animal models to test hypotheses concerning the pathogenesis of this disorder. This experimental approach represents one of the cornerstones for the discovery of new anti-OA drugs, and agents have emerged from such animal model studies that are now the subject of clinical evaluation. This chapter will concentrate on the in vivo animal models used to study OA.

Animal models of inflammatory arthropathies (rheumatoid arthritis [RA]), such as collagen-induced arthritis (CIA) in mice, have proven predictive of clinical efficacy, as therapies that are beneficial in CIA have moved into clinical use with proven benefit in RA treatment in humans (e.g., anti-TNF and anti-IL-1treatments).8,9 To date, however, none of the available animal models of OA can truly be said to be similarly predictive, as no anti-OA therapies have yet been proven in human trials. In this chapter, we review the literature on the most frequently used animal models of OA, particularly with regard to their use for determining the pathophysiology of the disease process. Many of these models have been used to evaluate various forms of treatment, but the vast amount of literature relating to this will not be exhaustively reviewed in this chapter. We have included reports on OA models that have appeared since the previous edition was published either if they describe a novel pathophysiological mechanism or method for evaluation of a previously published model, or they include an entirely new model. In the interests of brevity, many of the older citations have been deleted and readers are referred to previous editions for details.10 We have confined our review to models of OA in weight-bearing appendicular joints and thus have not included the temporomandibular or spinal facet joints although the disease processes are likely to be similar. The models are divided by the method of induction rather than the animal used. It is important to keep in mind inherent

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physiological differences that may exist between species that could influence the comparison with human disease. For example, adult rodents (rats, mice) do not express MMP-1, a major collagenase implicated in human disease,11,12 and their aggrecan core protein lacks the extended keratan sulfate binding region of other species including humans.13

Induction of Osteoarthritis by Injection of Compounds into Joints

A variety of agents, when they are injected intra-articularly into animal joints, elicit pathologic changes that show some resemblance to those seen in OA. Whereas two or three daily injections of physiologic saline into rabbit joints produced a decrease in the aggregation of cartilage proteoglycans,14 five daily injections of 10% saline provoked synovial hyperplasia, cartilage hypertrophy, and osteophyte formation after 2 months.15 Corticosteroids are known to have detrimental effects on the metabolism of human cartilage,16 and when high doses of these agents are administered intra-articularly to mice17 or rabbits,18,19 experimental arthropathies generally result. In hydrocortisone-injected rabbit joints, cartilage was depleted of hyaluronan, which may lead to a reduction in the ability of proteoglycans to aggregate and subsequent diffusion out of the cartilage matrix.20 Studies in horses have further demonstrated the potential detrimental effect of intra-articular corticosteroids on long-term cartilage metabolism and biomechanical properties.21,22,23 This chondrodestructive effect of some corticosteroids in animal models has raised the question of their indiscriminate use in clinical practice; however, these studies using normal joints do not mimic the disease situation, where the benefit of modulating the inflammatory process may outweight the detrimental effects. Co-administration of hyaluronan with corticosteroids was found to decrease proteoglycan degradation and loss from equine cartilage.24

Postmenopausal women receiving estrogen replacement therapy have a decreased OA incidence,25 radiologic progression of their disease26 particularly in large joints,27 and decreased levels of cartilage and bone collagen breakdown biomarkers.28 This is consistent with the observation that ovariectomy increased cartilage collagen breakdown and erosion in rats,29,30 inflammatory arthritis severity in DBA/1 mice,31 and surgically induced OA in sheep.32 However, intra-articular administration of estrogen induced degenerative changes in cartilage that resembled human knee OA when it was given at 0.3 mg/kg/day in mice33 and rabbits.18,33 It was noted in subsequent studies34 that estrogen receptors were upregulated in the femoral but not in the tibial cartilages of rabbit knees with estradiol-induced OA.

Models of OA directed toward selective degradation of the cartilage extracellular matrix have been developed by the use of intra-articular injections of proteolytic enzymes such as papain, trypsin, hyaluronidase, and collagenase in mice, rats, and rabbits (see review by Pritzker35). The mechanisms responsible for cartilage degradation in these models, particularly those in which papain or trypsin was injected, may deviate significantly from those that normally occur in the human disease because these proteins elicit an acute inflammatory reaction that may also contribute to cartilage destruction. Intra-articular injection of collagenase has been acknowledged to provoke additional joint instability by degrading the surrounding capsule and ligaments as well as by directly cleaving the cartilage collagen.36 Studies with C57Bl10 mice injected intra-articularly with bacterial collagenase demonstrated correlations between the degree of instability of the joint, the amount of cartilage damage, and the size of the osteophytes formed.37,38,39 Activation of the synovial macrophages also plays a pivotal role in osteophyte formation and fibrosis in this model.40

Intra-articular monosodium iodoacetate, an inhibitor of cellular glycolysis, has been used to induce OA-like cartilage changes in joints of hens, mice, guinea pigs, rats, rabbits, and horses.10 Cartilage lesions appeared in all species with marked loss of safranin O staining, indicating depletion of proteoglycans that is associated with an increase in aggrecan proteolysis by aggrecanases (ADAMTS) and matrix metalloproteinases (MMPs).41,42,43 This model was used to show that cartilage lesions in rat joints could be detected by scanning acoustic microscopy44 and ultrasonography45 and that the lesions could be ameliorated by MMP-inhibitors46 or by exercise in guinea pigs.42

Models of cartilage degeneration have been induced by intra-articular injection of specific cytokines, such as interleukin-1 (IL-1)47,48 and transforming growth factor- ,39,49,50 in both rabbits48,50 and mice.39,47,49,51 Intra-articular IL-1 injection in mice following immunization with methylated bovine serum albumin induces a transient inflammatory arthropathy more characteristic of RA rather than OA.52,53 Many other compounds, such as carrageenan and zymosan, when they are given by intra-articular injection, elicit degenerative changes in joint tissues; however, these substances also elicit an early acute synovitis and hence are relevant to inflammatory arthropathies more than to OA. In both rabbits54 and horses,55 intra-articular injection of autogenous cartilage particles led to cartilage degeneration over time. The interaction of these immunogenic particles with the synovial macrophages was considered to be responsible for the ensuing synovitis and subsequent joint disease. Oral quinolones induce cartilage lesions in young animals of a number of species, including rats,56 guinea pigs,57 dogs,58 and rabbits.59 The pathologic change in cartilage may be associated with chelation of magnesium60,61 and the changes are reported to be similar to human OA except that osteophytes do not develop in this model.59

Immobilization Models of Osteoarthritis

That articular cartilage requires joint motion and loading to maintain its normal composition, structure, and function is now widely accepted.62,63,64 Immobilization of a limb has been shown to induce atrophic changes within the articular cartilage of the joint, which include thinning,63,64 increased hydration,62,63,65,66 reduced proteoglycan content,62,63,64,65,66,67,68,69,70 altered proteoglycan structure,62,63,65,68 decreased proteoglycan

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synthesis,62,64,66,67,71 and increased collagen content and synthesis.65,68,72,73 Increased synthesis of prothrombin by chondrocytes may contribute to the cartilage remodeling and thinning observed in immobilized rat joints.74 Because many of these cartilage changes are similar to those described for human OA joints, limb immobilization has been used as a model particularly for studying the process of cartilage degeneration and more recently evaluation of potential biomarkers75 and anti-arthritic therapies such as chondroitin sulfate.76 However, fundamental morphologic differences in cartilage have been noted that may diminish the usefulness of the immobilization models. In OA cartilage, chondrocytes proliferate into clones or nests, often remaining active into the late stages of the disease. In contrast, chondrocytes within cartilage of immobilized joints do not form clones but undergo necrosis, particularly if there is no residual movement within the splint.77 This response of cartilage most likely results from impaired nutrition of the chondrocytes in the immobilized joint because of the absence of movement and loading.78 If a limited range of motion is allowed in the immobilized limb, however, the extent of cartilage degeneration is markedly reduced.66 Early work with immobilization models of OA in various species including rat, rabbit, and dog has been reviewed by Troyer79 and in the previous edition of this chapter.10

Models of Spontaneous Osteoarthritis

Naturally occurring OA is known to manifest spontaneously in a number of animal species. Selected studies using mice, rats, guinea pigs, and macaques are summarized in Table 5-1. Some breeds of dogs, including Labradors, German shepherds, and beagles, also develop OA with age, but this is generally secondary to hip dysplasia.107 In the spontaneously developing OA in dogs, a common pathologic feature of the early disease is a greater degree of synovitis and fibrosis of the joint capsule than is reported for human OA.108,109 A spontaneous decrease in afferent joint nerves with aging in Fisher 344 rats, and worsening of age-related OA with joint denervation in this species, suggested that loss of neuromuscular control and subsequent aberrant loading may be associated with spontaneous OA.110

Many inbred strains of mice develop spontaneous OA with age, including STR/ORT, BALB/c, DBA/1, and C57BL/6 (see Table 5-1). The incidence of the disease varies with strain and sex but can be as high as 90% in aged mice. Characteristic features of OA progression in these models include joint space narrowing, osteophyte formation, focal cartilage lesions, and decreased staining for cartilage proteoglycan. Although aging is a high-risk factor for OA in these models, the morphologic changes arising from the aging process alone have not been satisfactorily addressed. As with age-related OA in rats, loss of joint innervation has been implicated in spontaneous OA in C57BL6Nia mice.111 In some strains of mice such as DBA/1 and STR/ORT, OA is largely confined to the male gender and has been shown to depend on the presence of testosterone and aggressive behavior.80 The development of refined immunohistochemical techniques, computer-assisted digital image analysis, and advances in molecular biology investigation methodologies (in situ hybridization, genome wide microarray, etc.) has allowed the small amount of joint tissue from mice to be thoroughly investigated. Upregulation of chondrocyte expression of different matrix molecules, cytokines and MMPs, and proteolysis of collagen and aggrecan by MMPs and ADAMTS enzymes in a similar manner to human OA has been demonstrated in spontaneous OA in STR/ort mice.82,83,84,112,113

Research with spontaneous OA in guinea pigs has mostly been confined to the Hartley or Dunkin-Hartley strain (see Table 5-1), which has been widely used as an OA model in recent years. These animals have visible cartilage lesions by 3 months of age and a high incidence of bilateral knee OA by 12 months with subchondral bone sclerosis.90 Magnetic resonance imaging (MRI) has been successfully used to study this species,94 and there is enough joint tissue available for mRNA expression studies.11 Disease progression has been slowed by diet restriction91 and exercise modification114 demonstrating the role of mechanical factors in the disease process. It has been suggested that altered subchondral bone remodeling97 and abnormalities in the cruciate ligament115 may precede and lead to cartilage erosion in this animal model. However, changes in chondrocyte metabolism with ATP depletion and increased NO production have also been found preceding and in association with OA onset.116 This naturally occurring model has proven useful for evaluating potential therapies.117,118

Both rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques show a high incidence of spontaneous OA (see Table 5-1); its epidemiology and joint pathology resemble those of OA in humans.100 OA changes have been noted separately from those due to aging98 and, like the guinea pig (see above), both cartilage metabolic changes105,119 and subchondral bone mineralization abnormalities106 are implicated in the disease. In female macaques ovariectomy worsens the cartilage lesions and this can be inhibited by estrogen replacement therapy.120 The joints are also of a sufficient size for radiologic, histologic, and biochemical studies, and the prevalence allows the use of age-matched non-OA controls.99 However, because these animals are free ranging and have an extended life span (18 to 30 years), studies may require years for completion and may be influenced by uncontrollable environmental factors. Ethical and financial considerations make widespread use of this model unlikely.

Osteoarthritis in Genetically Modified Mice

The mouse is a convenient species for genetic modification (GM), and a number of spontaneous and engineered mutants have been studied that have, among their phenotypic abnormalities, an increased incidence of spontaneous OA (recently reviewed by Helminen et al.121). A selection of GM mice that have an increased incidence of OA or OA-like joint disease is given in Table 5-2. Homozygous deficiency in the major structural components of cartilage such as collagen II and its associated

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minor collagens IX and XI, or components of the proteoglycan aggregates (aggrecan and link protein), are usually lethal during embryogenesis or in the early postnatal period. However, it is noteworthy that while heterozygous deficiencies in the collagen network result in spontaneous OA-like changes in cartilage with aging, haplo-insufficiency of aggrecan or link protein does not cause joint cartilage abnormalities although intervertebral disc degeneration may be seen.157,158,159,160,161 Conversely, GM mice may also have a reduced incidence of spontaneous OA, or show protection in models of induced arthritis, and these animals are invaluable for advancing our

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understanding of the pathways involved in arthritis development and defining novel targets for disease therapy.162,163,164 While GM mice with increased spontaneous OA are extremely useful for investigating the role of specific proteins or mutations in the pathophysiology of OA, their utility as more universal models for evaluating therapy of OA in general, as opposed to the disease induced by the specific genetic abnormality they carry, must be questioned.

TABLE 5-1 SELECTED STUDIES OF SPONTANEOUS OA IN ANIMALS

Species Age Findings Reference
DBA/1 mice 0-6 months old OA development at 4 months old only in males 80
STR/ORT mice 5-50 weeks OA in 85% of all male mice; MMP and aggrecanase activity increase and colocalize with advancing OA; MMP-2, -3, -7, -9, -13, and -14 gene expression upregulated in AC at all ages but only MMP-3 and -14 protein detected by immunolocalization; collagen cleavage evident only where AC surface fibrillation occurred; chondrocyte apoptosis by TUNEL correlated with severity of OA lesions 81,82,83,84,85,86
C57BL/6 mice 18 months old running Increased incidence and severity of OA changes in mice run 1 km/day, therefore running accelerated OA development; collagen degradation absent in areas of chondrocyte death 87, 88
C57 mice 6 and 8-12 months old Some heat shock proteins, interleukin-6, and interferon expression were upregulated; expression of other heat shock proteins and interleukin-1 was unchanged in AC 89
Hartley guinea pigs 2-30 months old OA AC lesions visible by 3 months increasing to >50% of medial tibial AC bilaterally by 1 year old, with subchondral sclerosis; severity of OA lesions was reduced by 40% at 9 months, 56% at 18 months on restricted diet. At 12 months OA on unprotected medial tibial plateau, lateral not affected; increased volume of AC and subchondral bone. Despite gross OA changes only moderate and focal collagen ultrastructure network disruption; no fibre thickening. MRI showed AC thickness increased over first 6 months then decreased, T2 relaxation times increased with time so more predictable AC OA indicator. At onset of OA, AC PG and collagen decreased, AC small and large PG synthesis decreased, water increased and AC PG degradation was unchanged. Collagenase 1 and 3 mRNA expression varied with age and compartment; focal areas of collagenase 1 and 3 proteins in matrix in AC at OA lesions; initial bone density higher 11, 90-97
Rhesus macaque 5-25 years old Young animals with OA had increased PG levels whereas old had decreased; collagen correlated with age in both normal and OA but lower in OA AC. OA changes progressive through life with high prevalence. OA frequency increased with age and parity (in females); epidemiology and histology resembled OA in man. Increased OA by histology correlated with increased collagen extractability 98,99,100,101
Cynomolgus macaque 5-30 years old High prevalence of OA lesions, subchondral bone changes common and severe, showing before AC changes; subchondral bone thickness of medial tibia correlated with severity of OA lesions and increasing weight; prevalence and severity of OA lesions increased with age. All chondrocytes in OA lesions stained positive for 1, 3 and 5 1 integrins; in normal cells only 5 1. Increasing OA associated with reduced response to IGF-1 by chondrocytes. The mineralized plate beneath the AC thickened, overmineralized calcified AC and subchondral bone worse with age and OA 102,103,104,105,106
AC = articular cartilage; IGF = insulin growth factor; MMP = matrix metalloproteinase; PG = proteoglycan.

TABLE 5-2 TRANSGENIC MODELS OF OA IN MICE

Genetic Modification Resulting Phenotype Reference
Spontaneous deletion in Col2a1 gene giving defect in the C-propeptide (Dmm) Chondrodysplasia and early onset OA 122, 123
150-bp deletion mutation in the Col2a1 gene (Del1) Develop OA in knee joints; cathepsin K upregulated at lesion sites; knee OA increased with exercise 124,125,126,127
A large internal deletion in the Col2a1 gene Chondrodysplasia and increased incidence of OA in 15-month-old animals 128
Heterozygous deletion of Col2a1 Normal cartilage PG content and thickness, increased superficial zone fibrillation (73% v 21%) in 15-month-olds, reduced with running 127, 129
Arg519Cys mutation in Col2a1 Chondrodysplasia and generalized OA by 2 months of age 130, 131
Truncated Col9a1 Mild chondrodysplasia, with increased incidence of OA; loss of PG by 4-6 months and progressive fibrillation and erosion of AC by 12-18 months 132, 133
Deletion of Col9a1 AC fibrillation, chondrocyte proliferation, and osteophytosis by 9 months 134
1-bp deletion in Col11a1 resulting in effective deletion (Cho) Heterozygous mice have loss of AC PG, increased type II collagen degradation and AC fibrillation with increased MMP-13 in knee by 3-6 months 135,136,137
Single or double knockout of biglycan and fibromodulin (fdn); double knockout of lumican and fdn Tendon mineralization, gait abnormality, increased joint laxity, and increased OA evident by 6 months of age 138,139,140,141,142
ADAM-15 knockout Increased loss of proteoglycan and AC erosion with synovial hyperplasia in knee joints at 12-14 months of age in male mice 143
MMP-14 knockout Bone development and growth abnormalities with early onset of marked synovial hyperplasia and arthritis at 1-2 months of age 144
Interleukin-6 knockout Increased knee OA in males but not females associated with decreased aggrecan synthesis and bone mineral density 145
Mig-6 knockout Abnormal gait by 1 month, early onset osteophytes and AC degradation 146
Unknown spontaneous mutation (B6C3F1) Ankylosing OA tiptoe walking, swelling of ankle joints, and radiographic and histologic findings of OA AC changes by 9 months old in 80% of males 147
Unknown spontaneous mutation mapping to chromosome 10 (twy) Autosomal recessive trait, tip-toe walking mouse with multiple osteochondral lesions and longitudinal ligament calcification; decreased AC PG staining and presence of degenerated collagen fibers by 4-8 weeks 148, 149
Defect in a copper transporting gene (Blotchy) Affects elastin and collagen cross-linking resulting in spontaneous OA 150
Tissue specific BMP receptor type 1a deficiency Under Gdf5 control no BMP receptor in developing joints retention of webbing, failure of joint formation, and premature AC proteoglycan loss and erosion 151, 152
alpha-1 integrin knockout Earlier onset of OA with increased PG loss, AC degradation and synovial hyperplasia from 4-10 months but not different from wildtype at 12-15 months 153
Postnatal overexpression of MMP-13 Aggrecan depletion, collagen proteolysis, fibrillation, and erosion of articular cartilage along with synovial hyperplasia after 5 months 154
Transgenic overexpression of bovine growth hormone Chondrocyte and synovial hypertrophy with cartilage fibrillation at 6 months 155
Truncated kinase-deficient TGF- type II receptor Musculoskeletal developmental abnormalities and progressive chondrocyte hypertrophy with cartilage fibrillation by 6 months of age 156
AC = articular cartilage; BMP = bone morphogenic protein; mig-6 = mitogen inducible gene 6; PG = proteoglycan; TGF- = transforming growth factor .

Surgically Induced Destabilization Models of Osteoarthritis

Anterior Cruciate Ligament Transection

Traumatic rupture of the anterior cruciate ligament (ACL) is a relatively common event in dogs, particularly in the larger breeds. As is the case for human ACL rupture, canine joints may become osteoarthritic unless they are stabilized surgically. Pond and Nuki165 and Gilbertson166 described a method of reproducing this injury experimentally in normal dogs by transection of the ACL with a 2-mm stab (blind) incision through the capsule without damaging the adjacent periarticular ligaments or tendons. This closed surgical procedure was employed by McDevitt and Muir167 to observe the biochemical changes that occurred in cartilage 3, 6, 9, and 48 weeks after surgery. Histologic studies confirmed the progression of cartilage damage with time, as assessed by loss of staining for proteoglycans, chondrocyte cloning, and increased surface fibrillation.168 These experimentally induced biochemical and histologic changes in joints of mongrel dogs were analogous to those observed in the naturally occurring disorder resulting from spontaneous rupture of the ACL.

In the years after the initial reports of McDevitt and Muir,167,168 a plethora of publications appeared using the canine Anterior Cruciate Ligament Transection (ACLT) model to generate data on cartilage metabolism, its composition and structure, the production of cytokines and inflammatory mediators by synovial tissues, and structural changes in subchondral bone (reviewed in Smith and Ghosh10). This model was also used to evaluate the effects of nonsteroidal anti-inflammatory drugs, corticosteroids, and potential disease-modifying OA drugs on cartilage and synovial tissue metabolism in OA (reviewed in Smith and Ghosh10). More recent studies using the ACLT model in dogs are summarized in Table 5-3, which also notes important criteria that can influence the rate of progression of OA with use of this surgical procedure. Of particular relevance are the weights of the animals used, their ages, and the post-ACLT duration and treatment. There are no reports of comparative studies on the outcomes of ACLT in different canine breeds. Because ACLT destabilizes the joint and increases the shearing (plowing) stresses on cartilage, joints of heavy breeds subjected to postsurgical exercise would be expected to incur more damage than joints of the smaller, lighter breeds, but again, this has not been confirmed experimentally. It is also clear from the biomechanical studies that weight bearing on the ACLT joint is diminished postoperatively, the contralateral and forelimbs carrying more of the body load than before surgery. This reduced mechanical loading of the ACLT joint retards the progression of cartilage and bone injuries. However, dorsal root ganglionectomy of the destabilized limb can bypass the physiologic protection of the injured joint, and O'Connor and coworkers206 have shown that rapid joint destruction occurs when dorsal root ganglionectomy is combined with ACLT.

Open Versus Closed Anterior Cruciate Ligament Transection

In the original procedure described by Gilbertson,166 Pond and Nuki,165 and McDevitt and Muir,167,168 the ACL was transected by the blind insertion of a scalpel blade through the joint capsule. It was apparent, however, that synovial inflammation generally accompanied this technique.207,208,209, Intra-articular bleeding, largely from the vessels serving the ACL itself, was thought to contribute to the synovitis. When electrocautery and irrigation were applied during ACLT in an open procedure, synovitis was reduced to 24% compared with 69% in open surgery in which precautions to prevent bleeding were not observed.210 Moreover, cartilage hypertrophy, chondrocyte cloning, and fibrillation 10 weeks after surgery were less prominent in the surgically cauterized group than in the noncauterized group. It may be concluded from these and other studies cited in Table 5-3 that open ACLT, when care was taken to minimize intra-articular bleeding and inflammation, resulted in a model of hypertrophic OA that progressed only slowly, possibly because of lateral stabilization of the transected joint by osteophyte formation as well as reduced weight bearing on the limb. This early hypertrophic phase of cartilage response after open ACLT evolved into the classic joint disease of OA, including full-depth cartilage erosion, after 4 to 5 years.211

Anterior Cruciate Ligament Transection in Small Animals

ACLT has also been undertaken in cats, rats, guinea pigs, rabbits, and mice. These studies are summarized in Table 5-3. In small animals, frank cartilage lesions and synovitis develop much more rapidly than in larger animals. Whereas this offers potential advantages for experimental evaluation of antiarthritic preparations, the relevance of these rapidly progressive changes to the human disease may be diminished. Nevertheless, it is evident that OA resulting from ACLT in rats and rabbits involves changes in both the cartilage and subchondral bone, which in rabbits can be monitored using MRI.194,195 ACLT induces biochemical changes in cartilage that mimic those observed in humans, including altered expression of collagens and MMPs, increased loss of aggrecan (although the proteinases responsible for this in rats and rabbits have not been defined), and cleavage of type II collagen by MMPs.197,200,212.

Meniscectomy and Meniscal Injury/Destabilization Models of Osteoarthritis

The medial and lateral menisci are crescent-shaped fibrocartilaginous wedges interposed between the femoral condyles and tibial plateau of diarthrodial joints. These structures perform important mechanical functions because

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they distribute up to 50% of the load applied to the joint; they increase its stability and congruence and enhance articular cartilage lubrication and nutrition by moving synovial fluid over the joint surfaces.213,214,215,216,217, It is not unexpected, therefore, that mechanical failure or excision of these structures results in the imposition of abnormally high focal stresses on articular cartilage leading to premature degeneration and OA. This has been demonstrated both in long-term follow-up studies of patients after meniscectomy218,219,220, and in experimental animals10 (Table 5-4).

TABLE 5-3 SELECTED STUDIES USING ANTERIOR CRUCIATE LIGAMENT TRANSECTION (ACLT)

Species Post-ACLT Duration and Treatment Age or Body Weight Findings Reference
Dog Open Unilateral
Mongrel dog 4, 10, and 32 weeks 17-27 kg Aggrecan mRNA up at 10 and 32 weeks; collagen type II mRNA up at all time points-signals for transcription must be different 169
3 and 12 weeks 17-27 kg Decreased bone mineral density and structural changes in trabecular architecture of cancellous bone observed 3 weeks post-ACLT, worse at 12 weeks 170, 171
3 and 12 weeks 17-27 kg ACLT induced increased collagen type I and VI expression by menisci at 3 and 12 weeks; increases greater in medial than lateral 172
3 and 12 weeks 29-32 kg Aggrecan gene expression greater than collagen type II in control AC, reversed in OA AC at both timepoints 173
10 and 39 weeks 16-28 kg Micro MRI and polarised light microscopy can detect changes in AC collagen fiber orientation at 12 weeks 174
3 and 12 weeks 16-34 kg AC hypertropy worse at 12 weeks than 3 weeks; synovial fluid collagen type II markers, serum aggrecan and collagen II markers up at both timepoints 175
36 and 72 weeks Adult Significant trabecular bone loss with architectural adaptation by 36 weeks, less obvious at 72 weeks 176
Fox-hound 2 years 2 years old AC changes in expression of decorin and fibromodulin different in ACLT dogs to dogs with spontaneous OA 177
2-24 months 2-3 years old Some kinematic parameters were worse immediately after ACLT and did not improve with time, others worsened at 6-12 months post ACLT 178
2-24 months running 2-3 years old AC changes occurred early; decreased severity in longterm AC damage is associated with increased osteophyte formation and less severe medial meniscus damage 179
Dog Closed Unilateral
Dog 1-26 weeks Not published OA-like changes in AC included fibrillation, acellular zones in superficial layer synovial inflammation subsides within 1 week 165
1-48 weeks 15-30 kg Development of periarticular osteophytes at synovial margin commenced as early as 3 days and still progressed at 48 weeks 166
Mongrel dog 12 weeks 2-3 years old (20-25 kg) Chondrocyte apoptosis, caspase 3 and Bcl-2 markedly increased in OA AC 180
8 and 12 weeks 2-3 years old (22-27 kg) Osteocalcin increased at 8 weeks; increased alkaline phosphatase and prostaglandin-E2 at 12 weeks in subchondral and trabecular bone 181
12 weeks 20-25 kg Interleukin(IL)-1 converting enzyme and IL-18 levels increased in OA cartilage 182
8 weeks 20-25 kg Expression of MMP-13, cathepsin K, ADAMTS-4, ADAMTS-5, and 5-lipoxygenase increased in OA cartilage; decreased bone thickness with increased osteoclast staining of MMP-13 and cathepsin K 183, 184
Fox-hound 2, 10, and 18 weeks 19.0 28.5 kg Synovial fluid prostaglandin E2 correlated with clinical gait changes and may indicate lameness 185
Beagle 6, 12, 24, and 48 weeks 15-22 kg Early stable elevation of collagen I and II expression by chondrocytes; MMP-13 not elevated until 24 weeks and aggrecan and tenascin C until 48 weeks 186
6, 12, 24, and 48 weeks 15-22 kg MRI revealed subchondral bone edema in posteromedial tibia after 6 weeks, followed by erosion of AC after 12 weeks 187
Rabbit Open Unilateral
Rabbit 9 weeks 1 year old Menisci from ACLT knees contained high numbers of apoptotic cells and nitrotyrosine immunoreactivity 188
9 weeks Adult In transected knees, the compression modulus of the AC was reduced by 18%, while the permeability and electrokinetic coefficient were not detectably altered 189
3 and 8 weeks 12 months old ACLT caused matrix deterioration, cell cloning, clustering, and depletion in menisci; collagen type I and III were increased in medial and lateral; type II increased in medial 190
2, 4, and 9 weeks 9-10 months old MMP-1, -3, and -13 gene expression in AC and meniscus increased rapidly in OA, whereas expression of aggrecanases remained stable 191
4, 9, and 12 weeks 12 months old Osteophyte formation associated with expression of vascular endothelial growth factor (VEGF) in chondrocytes 192
2, 4, and 8 weeks 4.5 5.8 kg Micro-MRI reliably detects synovial effusion and osteophyte formation but not contour abnormalities of AC 193
4, 8, and 12 weeks 2.5 years old (4.6 0.4 kg) 3-D MRI and micro-computed tomography used to quantify AC damage, joint space, bone mineral density and calcified tissue changes 194, 195
9 weeks Adult Chondrocyte apoptosis increases with ACLT 196
11 weeks 3.7 1.4 kg Differing rates of regional AC proteoglycan loss detected 197
3, 6, and 12 weeks 4 kg Increased expression of hyaluronan receptor CD44v6 over time course of OA development 198
Other Open Unilateral
Rat 2-70 days 220-240 g Early proteoglycan depletion and collagen disruption at margins of AC after 4 weeks central regions showed surface fibrillation 199
2, 4, and 8 weeks 220-240 g AC degeneration starts at the AC surface and is associated with localized expression of collagen type II degradation products 200
2 and 4 weeks exercise 8 weeks old Beneficial effect of slight and moderate but not intense exercise on AC lesions, heat shock protein 70 expression, and chondrocyte apoptosis 201
2 and 10 weeks 20 weeks old ACLT increased serum cartilage oligomeric matrix protein (COMP) levels, urinary C-telopeptide, and deoxypyridinoline 202
1, 2, 4, 6, and 10 weeks 10 weeks old Subchondral bone resorption by 2 weeks before AC thinning; osteophytes by 10 weeks 203
Guinea pig 1-8 months 40 days old ACLT progressively increases OA histopathological changes; osteophytes first visible at 3 months 204
Cat 16 weeks and 5 years 2-22 years Age related decrease in cancellous bone mass and subchondral plate thickness by 5 years exacerbated by ACLT 205
AC = articular cartilage; ADAMTS A disintegrin and metalloproteinase with thrombospondin motifs.

Small Animal Meniscectomy Models

Partial excision of the anterior portion of the medial meniscus was used by Moskowitz and coworkers251 to induce degenerative changes in rabbit joints. A rapid (2 to 3 weeks)

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loss of proteoglycans from cartilage, fibrillation, and erosion with osteophytosis at the inner prominence of the medial tibial plateau were the outcomes of meniscectomy in this species.252,253,254 This model was subsequently used to identify the disturbance in cartilage metabolism and composition during the development of OA and provided a means of assessing the effects of hormones and antiarthritic drugs on these changes.10,221,222 More recently, total medial meniscectomy in rabbits has been reported to induce OA changes in cartilage and bone which can be reliably detected by micro-MRI.193,223,224,225

TABLE 5-4 STUDIES IN MENISCECTOMY (MX) AND MENISCAL DESTABILIZATION (MD) MODELS OF OA

Species Mx Method Post-Mx Duration Age or Body Weight Findings Reference
Rabbit Unilateral partial medial Mx 2, 4, 8, and 10 weeks 8 weeks (2.0 2.5 kg) Increase in AC thickness from 4 weeks; AC eburnation, erosion, and osteophytes from 6 weeks 221
8 and 52 weeks 2.5 3.5 kg Parathyroid hormone-related protein increased in late OA AC in proliferating chondrocyte clones 222
Unilateral total medial Mx 2-52 weeks Various Mx caused decreased tibial bone mineral density as well as typical AC OA lesions. Swelling of AC (increase in height) detected by MRI was due to PG and cell loss in early OA. Micro-MRI reliably detects synovial effusion and osteophyte formation but not contour abnormalities of AC. Macroscopic and histologic AC degeneration at 2 weeks that correlated with collagen type II epitope in synovial fluid. 193, 223,224, 225
Guinea pig Unilateral partial medial Mx 1-42 weeks 0.6 0.8 kg Moderate to severe AC focal lesions by week 1; the contralateral joint was affected by 12 weeks. AC lesions first on medial tibial plateau then medial femoral condyle then lateral compartment. MMP inhibitor prevented loss of AC thickness but not PG loss. PPAR agonist reduced AC lesions and chondrocyte staining of MMP-13 and interleukin-1 226,227,228,229
Rat Partial Mx 20 and 45 days 150 g Disruption of Golgi complex in chondrocytes increases with time and OA 230
Medial meniscal transection Up to 32 days Adult Pain assessment over 28 days showed little hyperalgesia but increasing tactile allodynia 231
Mouse Medial MD 4 and 8 weeks 10 weeks No reduction of severity of AC destruction in ADAMTS-4 knockout mice compared to wild type but significant reduction of severity of AC destruction in ADAMTS-5 knockout mice 163, 232
Grey hounds Bilateral total medial Mx 6 months exercise Adult AC degeneration in all Mx joints; lower glycosaminoglycan levels and more extractible PGs in AC from mobile contralateral Mx joints than in Mx or control joints. Femoral head AC from Mx group had decreased hyaluronan levels and increased PG extractability; no change in collagen or uronic acid levels compared to non-Mx 233, 234
Mongrel Dogs Unilateral total medial Mx 12 weeks 25-35 kg AC tensile modulus decreased with no change in water or PG content. Reliable degenerative changes occurred Synovial fluid biomarkers altered with different acute and medium-term responses eg cartilage oligomeric matrix protein (COMP) 235, 236
Sheep Unilateral total medial Mx 6 months exercise 2 years old PG content down at 6 months in passive and active Mx group; low salt extract of PGs; PG aggregation and water remained high. Still early OA features (AC fibrillation, chondrocyte hypertrophy, matrix proliferation, marginal osteophytes) more marked in exercised group 237,238,239
Unilateral total lateral Mx     Lateral Mx induced higher PG loss from AC and lower PG synthesis rates than medial Mx. Mx increased ostoid volume and surfaces with increased labelling of subchondral bone; AC has higher Mankin score after Mx. Mx animals reduced loading of operated limb. PG synthesis lower in lateral than in medial compartment. Keratan sulphate-peptide levels in synovial fluid increase progressively after Mx. Lower PG synthesis and more PGs released in high stress areas of AC; AC had increased synthesis of decorin and biglycan and increased aggrecan breakdown and release 240,241,242,243,244,245,246
Bilateral total lateral Mx 3 months 8-10 years Higher AC lesion scores and lower AC PG content; bone mineral density unchanged 247
2 and 16 weeks 12-15 months AC biomechanical changes throughout joint; collagen organization more important to dynamic shear modulus than PG content; not important for phase lag 248
6 months 7 years Mx increased thickness and density of subchondral bone and serum osteocalcin levels 249
Grivet monkey Unilateral total medial Mx 21-252 days Young Loss of cells from superficial layer, decrease in PG content of AC, cloning of deep layer cells 250
AC = articular cartilage; ADAMTS A disintegrin and metalloproteinase with thrombospondin motifs; PPAR = peroxisome proliferators activated receptor gamma; PG = proteoglycan.

Meniscal surgery has been used to induce OA in other small animal species including guinea pigs, rats, and mice. Partial medial meniscectomy in guinea pigs induces focal cartilage erosion within 1 week and by 12 weeks the contralateral (nonoperated) joint was also affected.227 Erosion of cartilage, but not proteoglycan loss, in the guinea pig meniscectomy model is abrogated by inhibition of MMPs.226 In the rat, meniscal transection has been shown to be a useful model to study the pain and hyperalgesia associated with joint destabilization.231 In mice, destabilization of the medial meniscus has recently been used to identify ADAMTS-5 and not ADAMTS-4, as the primary aggrecan-degrading enzyme in this species.163,232

Negating the weight-bearing function of the meniscus through the various surgical procedures consistently induces OA in small animals. However, the limited joint tissue available restricts the analyses that are possible, e.g., topographical differences in cartilage metabolism and biomechanics.255 Use of large animal models of meniscal surgery would overcome these deficiencies.

Large Animal Meniscectomy Models

In 1936, King256 demonstrated that medial meniscectomy in dogs caused early degenerative changes in articular cartilage, the extent of which was proportional to the amount of tissue excised. Cox and associates257 confirmed the findings of King256 but also compared the outcome of total unilateral meniscectomy with partial meniscectomy in which the outer rim was preserved. Animals were sacrificed at postoperative intervals of 3 to 10 months, and the results showed that the extent of joint damage, which included increased synovial fluid volume, synovitis, and focal erosion of cartilage, was proportional to the amount of meniscus removed. Ghosh and coworkers233,234 undertook unilateral medial meniscectomy in greyhounds and noted that postoperative immobilization of the joint decreased the extent of cartilage degeneration234 and meniscal regrowth233 (Table 5-4). Despite the advantages of using purebred dogs, economic and public antivivisection considerations associated with the use of these animals prompted the search for alternatives. Merino sheep, widely used wool- and food-producing animals, were therefore subjected to meniscectomy, and the joints were examined to determine whether the animal was a suitable model of OA. Initial investigations showed that unilateral medial meniscectomy produced hypertrophy of cartilage and only moderate fibrillation 3 months after surgery. However, marginal osteophytes, cell cloning, and subchondral bone changes were more evident after 6 months.237,238,239,240,258 As with the canine ACL model, progression of the hypertrophic phase to the stage when full cartilage lesions occurred was a slow process and was consistently observed only after 24 months.259 The rate of progression could be accelerated, however, by maintaining the animals on a regular weight-bearing exercise program.239

In human joints, the lateral meniscus protects a larger area of the tibial plateau articular cartilage than does the medial meniscus in its compartment.260 Because the anatomic features of human and ovine joints are essentially the same and the menisci perform similar functions,261

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it was reasoned that removal of the lateral meniscus of ovine joints would impose higher focal stresses on cartilage than occurred after medial meniscectomy. Consistent with this, cartilage explant cultures derived from the laterally meniscectomized animals displayed a greater loss of proteoglycans and a lower synthesis rate than in the corresponding cartilage cultures from joints of animals who were subjected to medial meniscectomy.240

In both unilateral medial and lateral meniscectomy models, gait analysis243,258 and metabolic studies of cartilage of the nonoperated contralateral limb242 showed that weight bearing on this joint was different from that in control animals not undergoing meniscectomy. This disparity most likely arose from the innate protective mechanisms that would prompt the animal to favor weight bearing on the side that was not operated on as well as on the forelimbs. From these observations, it was deduced that the contralateral joints of unilaterally meniscectomized sheep could not be used as control joints. This view was consistent with reports of others who used the canine ACLT model.262 Collectively, these observations have led to a further modification of the ovine model whereby bilateral lateral meniscectomy was undertaken to compel the animals to distribute their body weight equally on both hind limbs. This procedure also provides two experimental joints from each animal, thereby enlarging the scope for histopathologic, biochemical, and biomechanical investigations of cartilage, synovium, and subchondral bone.

TABLE 5-5 SELECTED STUDIES USING OTHER SURGICAL MODELS OF OA

Species OA Induction Method Post-surgery Duration Age or Body Weight Findings Reference
Rabbit Resection of ACL and MCL 4-12 weeks 3.0 3.5 kg OA changes by 4 weeks persisting through to 12 weeks; friction coefficient of joint significantly increased 263, 264
Partial medial Mx; resection of MCL 4 and 16 weeks 3 kg Proteoglycan content of AC decreased at 4 weeks, increased at 6 weeks 265
Guinea pig Resection of ACL, PCL, and MCL 21 weeks 0.5 0.6 kg Less OA pathology (AC pitting, ulceration, eburnation) with vitamin C supplementation; ACLT caused higher AC acid phosphatase 266
Rat Resection of ACL, PCL, and MCL 2, 4, and 6 weeks 150-200 g Changes in distribution of protein kinase C isoenzymes in cells of subchondral bone in OA joints 267
Resection of ACL, MCL, and Mx 1-10 weeks 10 weeks Bone loss and dull AC surface within 2 weeks; osteophyte formation by 6 weeks; bone eburnation by 10 weeks 203
MD; resection of MCL 1, 2, 3, and 6 weeks 300-350 g Increased depth of AC lesion over time, less increase in extent of lesion; early OA lesions detected by optical coherence tomography (OCT) 268, 269
0-42 days 7-9 weeks Progressive pattern of cartilage damage resembling human OA lesions 270
6 weeks FGF-18 300-375 g Fibroblast growth factor-18 (FGF-18) induced dose-dependent increases in AC thickness and reduced AC OA scores 271
Mouse Partial medial Mx; resection of MCL 4 days-4 weeks 25-30 g Gene deletion of either interleukin (IL)-1 , IL-1 -converting enzyme, iNOS, or MMP-3 accelerated development of OA 162
Combinations of Mx and ligament transection 2, 4, and 8 weeks 18-22 g Increasing OA scores with increasing instability. Bilateral Mx plus all ligaments transacted gave AC destruction by 2 weeks and osteophytes by 4 weeks. ACLT only gave partial AC destruction by 8 weeks. Collagen type X and MMP-13 induced early in OA. 272
Beagle Grooved AC and limb loading 3-40 weeks 10-15 kg Characteristic OA progression in AC observed at 10 weeks not evident at 3 weeks; mild synovial inflammation present; model has no permanent joint instability 273, 274
AC = articular cartilage; iNOS = inducible nitric oxide synthase; MD = meniscal destabilization; Mx = meniscectomy.

Other Surgical Models of Osteoarthritis

Numerous studies have used combinations of joint ligament transections with and without meniscal surgery to induce OA in rabbits, rats, guinea pigs, and mice (Table 5-5). Hulth and

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coworkers275 employed medial meniscectomy in rabbits but further destabilized the joint by severing the medial collateral ligament (MCL), ACL, and posterior cruciate ligament (PCL). The joint disease that developed was characterized by extensive osteophytosis and full-depth cartilage lesions. Columbo and associates276 undertook partial lateral meniscectomy in rabbits but also sectioned the sesamoid and fibular collateral ligaments. The procedure produced more consistent OA changes in rabbit joints276 and was subsequently used to evaluate the effects of a plethora of antiarthritic drugs on the development of cartilage lesions.10 The severity and speed of onset of OA following combination destabilization procedures in rabbit joints does not parallel the human disease, however, and may limit the relevance of such models.

In the rat and mouse, MCL transection has been combined with meniscal transection/destabilization.162,268,269,270,271 It is likely that the OA changes induced in this model (at least in the rat) are due solely to the meniscal surgery; as in a limited comparison, MCL transection alone did not cause any disease.270 Combining ACLT and medial meniscectomy in rats resulted in more extensive and earlier osteophytosis than ACLT alone.203 With increasing combinations of ligament transection and subsequent joint instability in mice, a similar worsening pattern of OA progression and bone remodeling was observed.272 In line with earlier comments in the rabbit, the severity and speed of joint destruction in mouse joints with multiple destabilizations limits their comparison with human disease, and to date no studies have demonstrated genetic or therapeutic modulation of such severe OA.

Tibial osteotomy277,278,279, and paw amputation64 in dogs confirmed the importance of weight bearing for the maintenance of cartilage integrity. Lameness induced by gluteal myectomy in Hartley guinea pigs 280 also caused OA changes in the knee joints; however, because these animals are predisposed to spontaneous OA (see earlier), other factors may have contributed to disease progression. Cartilage defects have been surgically produced in rabbit,281,282 dog,273,274,283 sheep,284 and horse285 knee joints, resulting in post-traumatic OA-like changes in joint tissues.

Miscellaneous Models of Osteoarthritis

A number of other techniques have been used to induce OA-like changes in joint tissues. Because the incidence of OA in humans is known to be associated with certain occupations that require repetitive mechanical activities,286 animals have been subjected to a variety of protocols in an attempt to reproduce stress-related changes in their joints. Rabbits running uphill on a treadmill for 5 days showed changes in cartilage proteoglycan content and synthesis.287 Similar experiments have been undertaken with beagles,70,288 but long-term moderate running exercise (4 km/day) failed to cause cartilage degeneration; the tissue remained essentially normal except in joint regions of high weight bearing, where it showed signs of hypertrophic change. Horses maintained on treadmill running demonstrated overload arthrosis in fetlock joints;289 high-stress treadmill training of standardbred horses for 8 weeks increased the degradation of aggrecan but increased the synthesis of decorin in cartilage explants sampled from the radial facet of the carpal joint.290 Changes in weight bearing have also been induced by repetitive impulse loading to rabbit joints291,292,293 and transarticular loading of dog joints.294 These techniques appear to cause excessive macrostructural damage to cartilage, such as the formation of deep clefts and fissures into the superficial and radial zone, but OA-like changes appear only after 6 months.294

Summary and Conclusions

Osteoarthritic changes have been induced in the joints of a large number of animal species by use of a wide range of experimental techniques. The rate of progression of OA lesions in these models is highly variable, being dependent on the species of animal and its age, sex, weight, and the type of housing and care used after the arthropathy has been induced. Moreover, the ostensibly same animal model may produce different outcomes in the hands of different investigators (e.g., ACLT in dogs, in which open and closed surgical methods are both widely employed). Using undefined or diverse genetic backgrounds of animals (e.g., mongrel compared with a single species of dog) not only increases the variability within experiments but makes comparisons between research facilities more difficult. Because animal models are now routinely used to evaluate potential therapeutic modalities for treatment of OA, it is clearly important to standardize the techniques and species employed to induce the arthropathy. Moreover, disease- or structure-modifying OA drugs are now under active development, but there is as yet no consensus on the most appropriate models to be used to identify such agents or indeed what pharmacologic activities the agents should possess to qualify them for inclusion under this classification. A great deal can be learned from OA models in small animal species, particularly with the use of powerful GM techniques in mice. However, in large animals, the increased load bearing more closely mimics human joints and, along with the potential to evaluate regional differences within a single joint, may make these species more physiologically relevant as models. Although we are of the opinion that large animal models of OA offer distinct advantages over rodent models, we recognize that economic and other considerations may preclude their use in many laboratories. A likely and logical approach is that promising compounds identified from in vitro and genetic (mouse) studies will be tested in high throughput small animal models. Those that prove useful in such preliminary studies can then be manufactured in sufficient quantities to be tested and validated in a large animal model.

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Osteoarthritis. Diagnosis and Medical. Surgical Management
Osteoarthritis: Diagnosis and Medical/Surgical Management
ISBN: 0781767075
EAN: 2147483647
Year: 2007
Pages: 19

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