Journal of Postgraduate Medicine
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Year : 2014  |  Volume : 60  |  Issue : 3  |  Page : 309-317  

Arthritis, a complex connective and synovial joint destructive autoimmune disease: Animal models of arthritis with varied etiopathology and their significance

SR Naik, SM Wala 
 Department of Pharmacology, Sinhgad Institute of Pharmaceutical Sciences, Lonavala, Pune, Maharashtra, India

Correspondence Address:
Dr. S R Naik
Department of Pharmacology, Sinhgad Institute of Pharmaceutical Sciences, Lonavala, Pune, Maharashtra


Animal models play a vital role in simplifying the complexity of pathogenesis and understanding the indefinable processes and diverse mechanisms involved in the progression of disease, and in providing new knowledge that may facilitate the drug development program. Selection of the animal models has to be carefully done, so that there is morphologic similarity to human arthritic conditions that may predict as well as augment the effective screening of novel antiarthritic agents. The review describes exclusively animal models of rheumatoid arthritis (RA) and osteoarthritis (OA). The development of RA has been vividly described using a wide variety of animal models with diverse insults (viz. collagen, Freund«SQ»s adjuvant, proteoglycan, pristane, avridine, formaldehyde, etc.) that are able to simulate/trigger the cellular, biochemical, immunological, and histologic alterations, which perhaps mimic, to a great extent, the pathologic conditions of human RA. Similarly, numerous methods of inducing animal models with OA have also been described (such as spontaneous, surgical, chemical, and physical methods including genetically manipulated animals) which may give an insight into the events of alteration in connective tissues and their metabolism (synovial membrane/tissues along with cartilage) and bone erosion. The development of such arthritic animal models may throw light for better understanding of the etiopathogenic mechanisms of human arthritis and give new impetus for the drug development program on arthritis, a crippling disease.

How to cite this article:
Naik S R, Wala S M. Arthritis, a complex connective and synovial joint destructive autoimmune disease: Animal models of arthritis with varied etiopathology and their significance.J Postgrad Med 2014;60:309-317

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Naik S R, Wala S M. Arthritis, a complex connective and synovial joint destructive autoimmune disease: Animal models of arthritis with varied etiopathology and their significance. J Postgrad Med [serial online] 2014 [cited 2021 Feb 28 ];60:309-317
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Arthritis is mainly characterized by inflammation of the synovial tissue/membrane and accompanying varying degrees of degeneration of cartilage and bone erosion. However, the correlation between inflammation and progressive destruction is not fully understood with rheumatoid arthritis (RA) or other types of arthritis. [1] Therefore, it is essential to explore the state-of-the-art of techniques/methods for assessing precisely the inflammation, cartilage damage, synovial joint destruction, and bone erosion which would find the possible solutions to define/explain the characteristic features of the inflammation that initiates progressive destruction. The major signs and symptoms observed are joint pain, joint enlargement or swelling, stiffness, warmth, and redness of the skin around joints. The different types of arthritis affecting various sites are peripheral arthritis, axial arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, RA, fibromyalgia, systemic lupus erythematosus, osteoarthritis (OA), gout, and polymyalgia rheumatica. Considering the various arthritis disorders, we felt it is essential to focus on and project RA and OA due to their severity and irreversibility, which finally manifests as the colossal loss of human productivity and low quality of life, with a deep social and economic impact all over the world.

Rheumatoid arthritis

RA can be defined as a chronic inflammatory disease with systemic autoimmune component, and is mainly characterized by aggressive synovial hyperplasia, synovitis, progressive destruction of cartilage, and bone erosion with painful swelling of small joints, fatigue, prolonged stiffness, and fever caused by immune responses and specific innate inflammatory processes. RA causes premature mortality, deformity of joints, loss of function, loss of productivity, and low quality of life. The ethiopathology of RA is still not completely understood, and till date, there is no effective treatment to cure RA. However, phytochemicals, and biotechnologically and synthetically derived magic therapeutic bullets may be able to provide relief from its severity as well as the low quality of life, or cure the arthritic condition. [2],[3]


OA can broadly be defined as a heterogeneous condition of transient and progressive structural changes in joint tissues, especially articular cartilage, subchondral bone, synovium, and synovial fluid, resulting in the development of bony spurs and cysts at the margins of the joints, and also affecting chondrocyte metabolism and the composition of extracellular matrix. [4],[5] OA affects knee joints, hips, small joints of hands, spine, and joints associated with mild synovitis, causing pain and stiffness. Some of the critical paradigms associated with OA are: articular cartilage edema, fibrillation and erosion with concomitant proliferation of chondrocytes, decreased staining of matrix proteoglycans (PGs), subchondral bone thickening, deformation of the articular surface, osteophyte formation, synovial intimal cell hyperplasia, and synovial fibrosis. Increased formation of cytokines activates matrix metalloproteinases (MMPs), important proteolytic enzymes responsible for the degradation of cartilage and bone. [6] Considering the aforementioned characteristic changes in the cartilage and supporting tissue, bone erosion, and molecular alterations, and to understand the existence of a complex relationship between the different disease mechanisms, many animal models were developed for the purpose of therapeutic evaluation of novel anti-osteoarthritic agents. [7]

Animal Models of RA

Considering the occurrence of several pathophysiological events in RA, different animal models are simulated for evaluation and determination of the therapeutic efficacy of new molecules. Animal model of human disease can be defined as a homogenous set of animals which have inherited, naturally acquired, or experimentally induced biological process, amenable to scientific investigation that in one or more respects might resemble the disease in humans, and is used to understand the indefinable processes and the diverse mechanisms involved. [8],[9]

Collagen-induced arthritis

Collagen type II (CII) is a major autoantigen in RA, and the prevalence of CII-specific antibodies and T cells in the early phase of RA suggests CII-specific immunity plays a major role in the induction of inflammation in articular joints and causing joint destruction. [10],[11] Hence, collagen-induced arthritis (CIA) models (mice, rats, and monkeys) are used widely because the model is found to be similar to that of human RA, mainly in its clinical and biochemical (synthesis of proinflammatory cytokines, prostaglandins, leukotrienes, and MMPs), immunological (activation of macrophages and inflammatory cells, overexpression of major histocompatibility complex II molecules, and enhanced cytokine production), and radiological and histologic aspects (inflammatory cell/leukocyte infiltration, inflammation of synovial joints, destruction of cartilage, bone erosion, and joint space narrowing). [12]

Induction of arthritis

The CII emulsion is prepared by mixing equal volumes of CII in 10 mM acetic acid and incomplete Freund's adjuvant. Then, 100 μg and 500 μg of CII emulsion are injected subcutaneously at the base of the tail of DBA/1J mice and Sprague-Dawley rats, respectively, on day 0 and day 7 for the induction of arthritis. All the symptoms of arthritis are observed between 12 and 14 days after CII emulsion administration. The various biological parameters, viz. paw volume, ankle diameter, grip strength, motility of joints, and pain threshold, are studied during arthritis development. The effects of test substances are assessed on 14-45 days by evaluating the various biological parameters mentioned above with visual (a score of 0-4) scoring system. The antiarthritic activity can be evaluated by prophylactic as well as therapeutic treatment. At the end of the experiment, radiographic analysis of normal and arthritic hind legs is performed using X-ray technique.

The radiological criteria considered are: 0, no tissue swelling or bone damage; 1, tissue swelling and edema; 2, joint erosion; 3, bone erosion; and 4, osteophyte formation. The radiology scores for both hind paws are used to calculate the arthritic index. Various antioxidants (lipid peroxides, myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase, glutathione, nitric oxide), serum lysosomal enzymes (cathepsin D, lactate dehydrogenase, β-glucuronidase), metabolic products of the connective tissue (hydroxyproline, sialic acid, N-acetyl-β-d-glucosaminidase), intermediary energy metabolites (mitochondrial ATPase, succinic dehydrogenase), and polyamines and proinflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β)] in edema tissue and serum are the important biochemical indicators for antiarthritic drugs. [13],[14],[15],[16],[17],[18],[19]

Freund's adjuvant-induced polyarthritis in rats

Experimental arthritis is induced in rats by the method of Newbould. [20] In the plantar region of right hind paw of each rat is injected subcutaneously 0.1 ml (10 mg/ml of heat-killed Mycobacterium tuberculosis suspension prepared in mineral oil) of complete Freund's adjuvant (CFA). Polyarthritis syndrome is manifested by the development of:

Primary lesions (injected paw),Secondary lesions (non-injected paws), andTertiary lesions (tail and ear nodules). The other characteristic features, viz. impaired motility of joints, grip strength, pain threshold, and gait, are found between 12 and 14 days after injection. These changes can be assessed by proper visual scoring system to determine the arthritic index. The evaluation of anti-arthritic activity of the test drug both prophylactically and therapeutically can be performed.

X-rays of hind legs of rats are taken prior to sacrifice in order to study the effect of test drug on cartilage degeneration, bone erosion, and pannus formation. Rats are sacrificed either on 15 th or 29 th day for studying the biochemical changes in blood and inflamed tissues, including histologic alterations.

Pristane-induced arthritis

The non-antigenic chemical, pristane (2,6,10,14- tetramethylpentadecane), is known to induce delayed onset of arthritis and unparalleled chronicity by involving CD4 + T cells, immunodominant environmental antigens, and heat shock protein 65 (hsp 65) and activating lymphocytes. [21] Intraperitoneal injection of pristane in the rodents induces chronic arthritis (onset from 60 to 200 days) that closely resembles RA. Alternatively, pristine-induced arthritis (PIA) can also be achieved in rats by intradermal injection of 150 μl at the base of the tail, which develops arthritis within 2-3 weeks and progresses with a relapsing course that persists for more than 6-10 weeks. The PIA is characterized clinically by joint swelling, pathologic alterations (polymorphonuclear cell infiltration and formation of pannus in affected joints), activated proinflammatory cytokines, and enhanced humoral/cellular responses to several putative joint autoantigens. [22],[23] Both PIA and RA are characterized by elevated levels of circulating rheumatoid factor, agalactosyl immunoglobulin G (IgG), cytokines [IL-1, IL-4, IL-6, TNF-α, and interferon gamma (IFN-γ)], glucose-6-phosphate isomerase, chondroitin sulfate B, collagen I, collagen II, aggrecan, and DNA of the connective tissue within 4-12 months post-pristane injection. [24] The development of arthritis is monitored by a macroscopic scoring system for four limbs with a scale ranging from 0 to 4, as mentioned earlier.

PG-induced arthritis

Aggrecan, a known cartilage-specific PG core protein, is used as an antigen to induce arthritis in rodents which exhibits a biological profile similar to that of collagen arthritis. PG aggrecan has also been reported to induce erosive polyarthritis and spondylitis in BALB/c mice, which is attributed to the G1 domain of the PG. [25],[26] PG-induced arthritis is directly related to the interaction between T cells (CD4 + T cells) and B cells, and these are found to be the major immune cells participating in the genesis of arthritis. [27],[28] Accumulation of PG-specific IgG in the cartilage and inflamed joints leads to loss of cartilage. Thus, the interaction between IgG containing immune complexes and FcγRs is the major factor in the progression of inflammation and development of arthritis.

The arthritis in female BALB/c mice (12-14 weeks old) is induced by intraperitoneal injection of 150 μg PG (obtained from human spondylitis/arthritic cartilage patients) prepared in dimethyldioctadecylammonium bromide. Subsequently, BALB/c mice received a booster dose of 100 μg PG at an interval of 3 rd and 6 th week and were observed for inflammatory reactions/arthritic symptoms (such as varied degrees of edema, erythema with ankylosis) scored on the basis of intensity on a scale of 0-4 in a blind fashion for every 2 weeks up to a period of 18 weeks and the arthritic index is calculated. Histopathologic alterations observed are:

Infiltration of mononuclear cell,Pannus formation, andMarginal cartilage erosions. At the end of 18 th week, the hind ankles of arthritic mice are isolated and joints are fixed in formalin, decalcified (5% formic acid), embedded in paraffin, and stained with hematoxylin and eosin. Mononuclear cell infiltration is measured under a microscope, which is solely responsible for the intensive proliferation of synovial macrophages and fibroblasts. The research findings reveal that though PG-induced arthritis is similar to CIA, it exhibits less degree of degeneration of connective tissues and joint ankylosis. However, the clinical features reported in human RA by radiographic analysis, scintigraphic bone scans, and histopathologic studies resemble the symptoms in mice model of PG arthritis. [29]

Cartilage oligomeric matrix protein-induced arthritis

Cartilage oligomeric matrix protein (COMP) is a 524-kDa homopentameric extracellular matrix glycoprotein, belonging to thrombospondin family. COMP is synthesized largely by chondrocytes, and is localized extracellularly and present in cartilage, tendon, vitreous of the eye, and vascular and smooth muscle cells. In adults, COMP is most abundantly found in the inter-territorial matrix of articular cartilage, and is a sensitive indicator of the progression of arthritis. [30],[31],[32]

RA is induced by immunization with COMP, which finally manifests as autoimmune arthritis due to cross-reactive immune responses to autologous mouse COMP. Further, COMP-induced arthritis largely relies on T cell recognition as well as major histocompatibility complex (MHC) molecules. COMP-immunized mice develop a strong and specific IgG response to COMP, increased B cells, CD4 + T cells, and absence of cytotoxic CD8 + T cells. This model develops symptoms analogous to human arthritic symptoms such as synovial hyperplasia, increased synovial volume, cellular infiltration, and the unique feature of a chronic relapsing disease phase observed mainly in females. [33]

Induction of arthritis

Mice are immunized initially by intradermal injection of 100 μg of COMP emulsified in 100 μl of CFA at the base of the tail. Subsequently (after 35 days), a booster injection of 50 μg of COMP in 50 μl of Freund's incomplete adjuvant is administered intradermally at the base of the tail. The mice are monitored three times a week for 160 days for the development of arthritis. Assessment of the number and degree of joints affected is performed by a macroscopic scoring system on a scale of 0-4 and the following are assessed:

Swelling and redness of one joint,Involvement of two joints,Involvement of more than two joints, andSevere arthritis of the entire paw. The histologic studies of the paws/hind limbs are performed by dissection, followed by decalcification and dehydration, and then by embedding in paraffin. Sections of 4 μm size are cut and stained with hematoxylin and eosin. Severe inflammation with infiltration of mononuclear cells in the synovial tissue, pannus formation, and destruction of adjacent cartilage and bone are the histologic findings. [34]

Avridine-induced arthritis in rats

Avridine [(N,N-dioctadecyl-N',N'-bis (2-hydroxyethyl) propanediamine], a potent synthetic non-immunogenic adjuvant, is used to induce arthritis in rats. Avridine-induced arthritis (AIA) is similar to collagen and Freund's adjuvant induced arthritis with respect to many pathophysiological symptoms. The development of arthritis is largely mediated by T cells and influenced by both MHC and non-MHC genes. [35] It is documented that LEW and DA rats are the most sensitive and develop severe arthritis with avridine. It is found that the infiltration of CD4 + T lymphocytes and MHC class II expression occurs prior to the development of arthritis.

Induction of arthritis

Avridine is solubilized in Freund's incomplete adjuvant and injected subcutaneously at a varied concentration, ranging from 3.75 to 7.5 mg/rat, either at the base of the tail or into the plantar region of hind paws of the rat. Development of arthritis was found to be 100% at 7.5 mg and 60-70% at 3.75 mg within 4 weeks period. Arthritis index is scored by visual scoring system on a scale of 0-4, observing the following parameters, respectively, in the four limbs:

Swelling and redness of one phalangeal joint,Two phalangeal joints and one larger joint,More than two joints, andSevere arthritis in all the paws. Paw edema can be measured by plethysmometer and swelling of joints (diameter of the joints) by a vernier caliper. The arthritic scoring can also be performed by histomorphologic and immunohistochemical analysis of the joints. [36]

Streptococcal cell wall-induced arthritis

Streptococcal cell wall (SCW)-induced arthritis is a widely accepted rat model because it exhibits many critical symptoms of human RA, viz. infiltration of polymorphonuclear cells, CD4 + T cells, macrophages, hyperplasia of the synovial membrane, pannus formation, and significant erosion of cartilage and bone. In this model, synovitis can be induced within 24 h with maximum swelling by intraarticular injection of the antigen into an ankle joint. A characteristic feature of this model is development of spontaneous response, which allows the precise analysis of both cellular and biological mechanisms. [37] The active participation of TNF-α, IL-1α, IL-4, nitric oxide synthase (NOS), cyclooxygenase, P-selectin, vascular cell adhesion molecule-1, macrophage inflammatory protein (MIP)-2, MIP-1α, and monocyte chemoattractant protein (MCP)-1 in SCW-induced experimental arthritis has been demonstrated. [38],[39],[40],[41]

Induction of SCW arthritis

Streptococcus pyogenes T12 gram-positive organisms are cultured overnight, and the cell walls are harvested, centrifuged at 10,000 g (contain 11% muramic acid), and then used for the induction of arthritis. Unilateral arthritis is induced in mice by intraarticular injection of 25 μg SCW prepared in 6 μl phosphate buffered saline (PBS) into the right knee joint, and the non-injected left knee joint is used as a control. The same injection is repeated on different days (0, 7, 14, and 21) to induce chronic arthritis. The degree of severity of inflammation in the knee joints is assessed by macroscopic scoring system. Full fledged joint inflammation is manifested on 28 th day. Histologic examination of the total knee joints indicates changes in patella and femur/tibia regions, which are accompanied by bone erosion, exudate formation, and infiltration of granulocytes. [38]

Formaldehyde-induced arthritis

An acute rat model of formaldehyde-induced arthritis is used for screening antiarthritic agents. Development of arthritis is attributed to the release of histamine, serotonin, and prostaglandin at the site of injection. The rats are injected with formaldehyde (0.1 ml of 2% v/v) into the subplantar region of the hind paws on 1 st and 3 rd days. The edema of the hind paw is measured daily for 10 days by plethysmometer. The manifestation of arthritis is assessed by various parameters, viz. hind paw edema, diameter of the ankle joint, joint motility, pain threshold, and grip strength. Similarly, the degenerative changes of cartilages and bone erosion are also evaluated by X-ray studies of the hind limbs. The histopathologic studies are also performed to see the cellular changes, pannus formation, and other degenerative changes of cartilages and bone. [42],[43]

 Animal Models of OA

Naturally/spontaneous occurring OA models

Virtually all the spontaneous animal models of OA are found to exhibit morphologic changes that resemble human OA conditions. Guinea pig, mouse, and nonhuman primate are considered to be the best spontaneous models of OA, and enable us to understand the slow progressive OA that may resemble human OA. The major advantage of such animal models is primarily due to their resemblesance to natural progression of the disease without any direct intervention or stimulation. The clinical symptoms and findings reported in spontaneous occurring OA models are outlined in [Table 1]. [44],[45],[46],[47],[48],[49]{Table 1}

Surgically induced OA

Various types of injuries to cartilage lead to OA in humans, which have been simulated in animal models by manipulating anterior cruciate ligament transection (ACLT) and meniscectomy model, with special reference to knee OA [Table 2]. [50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61] The disease progression is found to be more rapid in animal models than in humans, thus making the models less amenable to therapeutic intervention. However, cartilage damage observed in such models resembles human knee OA. Hence, these models have been used widely for evaluation of analgesics and structure-modifying agents. However, based on the observations, the use of rodents as the model is debatable as the disease is confined largely to knee joints.{Table 2}

Chemically induced OA

Intraarticular injections of diverse chemical agents (physiological saline, corticosteroid, estrogen, papain, collagenase, monosodium iodoacetate, quinolone antibiotics, etc.) induced acute inflammation with cartilage degeneration and degradation of extracellular matrix, which are found to be somewhat similar to those in human OA [Table 3]. [62],[63],[64],[65],[66],[67],[68],[69] In addition, the oxidative stress induces marked changes in enzymes that are closely participating in the progression of OA. This model is particularly beneficial for rapidly developing synovitis associated with pain and decreased motility of joints. In such models, no severe changes are observed at early stage of OA and the changes are also found to be reversible. Thus, apparently, such models seem to have specific advantage in the evaluation of nonsteroidal and steroidal anti-inflammatory drugs. Nevertheless, experimental findings of such animal models suggest the altered pathology does not fully represent human OA conditions.{Table 3}

Physical models of OA

Physical/biomechanical models of OA are the routinely used models to reproduce mainly sport traumatism and accidental traumas in humans and veterinary orthopedic research, respectively.

Surgical interventions (desmotomy, meniscectomy, deliberate patellar contusion or luxation, continuous immobilization, non-physiological overload) are the techniques used for induction of mechanical stress on articular cartilage and impaired congruency, motility, and joint instability. Such models induce rapid and severe cartilage degeneration than the spontaneous models. The deterioration due to physical alterations adversely affects the metabolism of chondrocytes of subchondral bone, leading to degeneration and damages. [70]

The Pond-Nuki model

The tearing and stretching of ligaments often result in the rupture of ligaments, leading to OA. Canine stifle surgical cranial cruciate ligament (CCL) resection proposed by Pond and Nuki [56] is a widely accepted model of OA. The method involves the mechanical instability that triggers pathophysiological alterations leading to OA in dog, which in many respects resembles human OA. However, clinical investigations on CCL of the knee failed to explain the probable cause for its spontaneous rupture without any trauma. Even though the clinical opinion differs, the onset of symptoms of OA is normally observed within 3-5 weeks after CCL rupture. [71] The resection can also be performed by percutaneous stab incision, open arthrotomy, and arthroscopically guided transection. [72] The physio-anatomical changes in bone, cartilage, and synovial membrane in dogs occur within a period of 16 weeks, which is akin to natural OA. [73] Onset of inflammation in synovial fluid is observed within 13 weeks of subjecting subchondral bone to focal alteration stress. [74] It causes significant changes in mineral density within 3-12 weeks, and is known to induce the activity of metalloproteinases.

Immobilization model

Immobilization is the most common orthopedic treatment practised clinically for musculoskeletal injury, deformity, and inflammation. Prolonged immobilization results in joint contracture and atrophy of muscle and bone. Experimental immobilization is used as a model for OA which triggers morphologic degeneration and biochemical changes in joint cartilage. Immobilization of hamsters for 3 months decreased the content of PG and synovial fluid volume in the stifle joints. [75] Torelli et al. have demonstrated that splint immobilization of the stifle joint in rabbits (12 weeks) developed OA, which is closely related to the morphologic and biochemical changes observed in cartilage and bone structure. [76]

Canine groove model

Canine model of OA is developed by damaging the articular cartilage of the weight-bearing areas of the femoral condyles in one knee, without damaging the subchondral bone, and without affecting joint stability. To trigger OA, the affected joints are loaded by fixing the contralateral control limb to the trunk of the dog temporarily. In this model, it is reported that within 10 weeks a characteristic change occurs in collagen metabolism, turnover of PG, MMP activity, and histoarchitecture alterations, viz. moderate cartilage destruction, fibrillation of the articular surface, and chondrocyte clustering. The degenerative changes represent the naturally occurring erosion in OA development with age, characterized by slow but steady progression of degenerative events with domination over the repair potential of the cartilage matrix. [77]

Mechanical overload model

Mechanical factors such as chronic overload and higher degree of sudden stress play a major role in the pathogenesis of the OA. The model is simulated by mechanical overloading on the hind limb of dogs to produce subchondral microfractures of the femoral condyle to initiate a characteristic degeneration of the cartilage. Overloading is found to be a risk factor for the wear and tear of joints both in animals and humans. In general, this method can be an intermediate between naturally occurring and surgically induced OA models. [78]

Hypermotility model

The objective of the model is to simulate a physical wear and tear of cartilage, which is generally much above its normal capacity for physiological movements and repair. The benefit of this model is to provoke articular cartilage alterations that resemble human OA. Pap et al. demonstrated eloquently the destructive effect of strenuous physical exercise on the structural alterations of joints in rats. Intracranial self-stimulation causes rats to run distances of approximately 15 and 30 km within 3 and 6 weeks in a revolving wheel. By the end of the trial period, a significant elevation of metalloproteinases along with concomitant loss of chondrocyte from the superficial cartilage layer is reported. [79]

Models of genetic modification

Transgenic or knockout mice models with altered expression of transcription factors, viz. MMP, angiogenic factors, or extracellular proteins, adequately provide information pertaining to the mechanism(s) that control or modulate cartilage development and pathogenesis of OA. To simulate OA lesion swiftly, surgical methods are used in transgenic mice.

Transgenic mice are a useful tool to understand the specific role of biomolecules and their pathways in the genesis of OA. It is difficult to accept that single gene defects are able to simulate OA in humans. Therefore, use of such animal models for evaluation of the effects of therapeutic agents on OA is questionable. The modifications of genes of growth factor signaling pathway (viz. Bmpr1a, TGF-β RII, Smad3, Ank, Npp1, α1 integrin, Runx2, Hif-2α, and miR-104) are involved in the development of OA with well-defined characteristic features such as cartilage degeneration/degradation, increased chondrocyte hypertrophy and progression, skeletal degeneration, cartilage erosion, crystal deposition, and increased osteophyte formation. Genetic manipulation of genes of extracellular matrix (viz. Col2a1, Col9a1, Col9a1, Col11a1, aggrecan, fibromodulin, fibromodulin/biglycan, and matrilin-3) may result in degenerative changes in cartilage, mild chondrodysplasia, tendon mineralization, and early-onset OA in adult mice. Similar genetic manipulation of the genes of proteinases (Mmp9, Mmp13, Adamts5, Timp3) and cytokines (IL-1β, IL-6, ICE, MK2, NOS2) are also reported to participate in the development of OA similar to that of humans. [80],[81],[82]


The simulation of animal models of arthritis is the major approach for understanding the cellular, molecular, biochemical, and pathologic events of the disorder. Among the arthritic disorders, RA and OA are the most complex destructive and immune origin crippling diseases. Till date, there are no effective therapeutic interventions for preventing as well as curing such diseases, largely due to the inability to simulate etiologically valid, identical animal models of human arthritis. However, in the present review, we have attempted to enumerate diverse animal models of RA and OA of a variety of species in order to gain a wider and perspective knowledge concerning the pathogenesis of arthritis, so that appropriate models can be adopted judiciously for efficient evaluation of novel therapeutic agents. Ostensibly, with the advantage of knowledge-based science, especially in molecular biology and biotechnology, we may perhaps be able to clinch success in identifying the complex events of arthritis and may provide impetus to develop more specific animal models of RA and OA. Such breakthrough might open up a new corridor for the development of effective and safe new-generation antiarthritic agents.


1Fex E, Jonsson K, Johnson U, Eberhardt K. Development of radiographic damage during the first 5-6 yr of rheumatoid arthritis. A prospective follow up study of a Swedish cohort. Br J Rheumatol 1996;35:1106-15.
2Brooks PM. The burden of musculoskeletal disease-a global perspective. Clin Rheumatol 2006;25:778-81.
3Zvaifler NJ. A speculation on the pathogenesis of joint inflammation in rheumatoid arthritis. Arthritis Rheum 1965;8:289-93.
4Hochberg MC. Epidemiologic considerations in the primary prevention of osteoarthritis. J Rheumatol 1991;18:1438-40.
5Moskowitz RW, Goldberg VM. Osteoarthritis. In: Schumacher HR, Klippel JH, Robinson DR, editors. Primer on the Rheumatic Diseases. Atlanta, GA: Arthritis Foundation; 1988. p. 171-7.
6van den Berg WB. The role of cytokines and growth factors in cartilage destruction in osteoarthritis and rheumatoid arthritis. Z Rheumatol 1999;58:136-41.
7Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets. Arthritis Rheum 2001;44:1237-47.
8Frenkel JK. Choice of animal models for the study of disease processes in man. Introduction. Fed Proc 1969;28:160-1.
9Richardson, JG. A primer of model systems. In: Richardson J, editor. Models of Reality. Mt Airy: Lomond Publications; 1984. p. 1-8.
10Kim HY, Kim WU, Cho ML, Lee SK, Youn J, Kim SI, et al. Enhanced T cell proliferative response to type II collagen and synthetic peptide CII (255-274) in patients with rheumatoid arthritis. Arthritis Rheum 1999;42:2085-93.
11Kim WU, Cho ML, Jung YO, Min SY, Park SW, Min DJ, et al. Type II collagen autoimmunity in rheumatoid arthritis. Am J Med Sci 2004;327:202-11.
12Kannan K, Ortmann RA, Kimpel D. Animal models of rheumatoid arthritis and their relevance to human disease. Pathophysiology 2005;12:167-81.
13Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Britti D, De Maio M, et al. Absence of endogeneous interleukin-10 enhances the evolution of murine type-II collagen-induced arthritis. Eur Cytokine Netw 2001;12:568-80.
14Chakradhar LV, Naik SR. Polyamines in inflammation and their modulation by conventional anti-inflammatory drugs. Indian J Exp Biol 2007;45:649-53.
15Lagishetty CV, Naik SR. Polyamines: Potential anti-inflammatory agents and their possible mechanism of action. Indian J Pharmacol 2008;40:121-5.
16Naik SR, Sheth UK. Studies on two derivaties of N-aralkyl-o-ethoxybenzamides: Part II -biochemical studies on their anti-inflammatory activity. Indian J Exp Biol 1978;16:1175-9.
17Naik SR, Sattur PB, Sheth UK. Studies on two derivatives of N-aralkyl-o-ethoxybenzamides: Part III-pharmacological and biochemical studies on their anti-arthritic activity in rat. Indian J Exp Biol 1979;17:1353-6.
18Naik SR, Naik PM, Chinwala TS, Valame SP, Sheth UK. Some biochemical effects of anti-rheumatic drugs. Biochem Pharmacol 1978;27:353-5.
19Kalyanpur SG, Pohujani S, Naik SR, Sheth UK. Study of biochemical effects of anti-inflammatory drugs in carrageenin induced oedema and cotton pellet granuloma. Biochem Pharmacol 1968;17:797-803.
20Newbould BB. Chemotherapy of arthritis induced in rats by mycobacterial adjuvant. Br J Pharmacol Chemother 1963;21:127-36.
21Bedwell AE, Elson CJ, Hinton CE. Immunological involvement in the pathogenesis of pristane-induced arthritis. Scand J Immunol 1987;25:393-8.
22Wilder RL, Remmers EF, Kawahito Y, Gulko PS, Cannon GW, Griffiths MM. Genetic factors regulating experimental arthritis in mice and rats. Curr Dir Autoimmun 1999;1:121-65.
23Wooley PH, Seibold JR, Whalen JD, Chapdelaine JM. Pristane-induced arthritis. The immunologic and genetic features of an experimental murine model of autoimmune disease. Arthritis Rheum 1989;32:1022-30.
24Hitsumoto Y, Thompson SJ, Zhang YW, Rook GA, Elson CJ. Relationship between interleukin 6, agalactosyl IgG and pristane-induced arthritis. Autoimmunity 1992;11:247-54.
25Finnegan A, Mikecz K, Tao P, Glant TT. Proteoglycan (aggrecan)-induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines. J Immunol 1999;163:5383-90.
26Zhang Y, Guerassimov A, Leroux JY, Cartman A, Webber C, Lalic R, et al. Arthritis induced by proteoglycan aggrecan G1 domain in BALB/c mice. Evidence for t cell involvement and the immunosuppressive influence of keratan sulfate on recognition of t and b cell epitopes. J Clin Invest 1998;101:1678-86.
27Banerjee S, Webber C, Poole AR. The induction of arthritis in mice by the cartilage proteoglycan aggrecan: Roles of CD4+ and CD8+ T cells. Cell Immunol 1992;144:347-57.
28Mikecz K, Glant TT, Buzás E, Poole AR. Proteoglycan-induced polyarthritis and spondylitis adoptively transferred to naive (nonimmunized) BALB/c mice. Arthritis Rheum 1990;33:866-76.
29Wooley PH, Siegner SW, Whalen JD, Karvonen RL, Fernández-Madrid F. Dependence of proteoglycan induced arthritis in BALB/c mice on the development of autoantibodies to high density proteoglycans. Ann Rheum Dis 1992;51:983-91.
30Oldberg A, Antonsson P, Lindblom K, Heinegård D. COMP (cartilage oligomeric matrix protein) is structurally related to the thrombospondins. J Biol Chem 1992;267:22346-50.
31Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, et al. Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem 1992;267:6132-6.
32DiCesare P, Hauser N, Lehman D, Pasumarti S, Paulsson M. Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon. FEBS Lett 1994;354:237-40.
33Carlsen S, Nandakumar KS, Bäcklund J, Holmberg J, Hultqvist M, Vestberg M, et al. Cartilage oligomeric matrix protein induction of chronic arthritis in mice. Arthritis Rheum 2008;58:2000-11.
34Holmdahl R, Jonsson R, Larsson P, Klareskog L. Early appearance of activated CD4+ T lymphocytes and class II antigen-expressing cells in joints of DBA/1 mice immunized with type II collagen. Lab Invest 1988;58:53-60.
35Vingsbo C, Jonsson R, Holmdahl R. Avridine-induced arthritis in rats; a T cell-dependent chronic disease influenced both by MHC genes and by non-MHC genes. Clin Exp Immunol 1995;99:359-63.
36Jonsson R, Tarkowski A, Klareskog L. A demineralization procedure for immuno histopathological use. EDTA treatment preserves lymphoid cell surface antigens. J Immunol Methods 1986;88:109-14.
37Esser RE, Stimpson SA, Cromartie WJ, Schwab JH. Reactivation of streptococcal cell wall-induced arthritis by homologous and heterologous cell wall polymers. Arthritis Rheum 1985;28:1402-11.
38Schimmer RC. Schrier DJ, Flory CM, Dykens J, Tung DK, Jacobson PB, et al. Streptococcal cell wall-induced arthritis. Requirements for neutrophils, P-selectin, intercellular adhesion molecule-1, and macrophage-inflammatory protein-2. J Immunol 1997;159:4103-8.
39Schrier DJ, Schimmer RC, Flory CM, Tung DK, Ward PA. Role of chemokines and cytokines in a reactivation model of arthritis in rats induced by injection with streptococcal cell walls. J Leukoc Biol 1998;63:359-63.
40McCartney-Francis N, Allen JB, Mizel DE, Albina JE, Xie QW, Nathan CF, et al. Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 1993;178:749-54.
41Sano H, Hla T, Maier JA, Crofford LJ, Case JP, Maciag T, et al. In vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis. J Clin Invest 1992;89:97-108.
42Owoyele VB, Adediji JO, Soladoye AO. Anti-inflammatory activity of aqueous leaf extract of Chromolaena odorata. Inflammopharmacology 2005;13:479-84.
43Kyei S, Koffuor GA, Boampong JN. The efficacy of aqueous and ethanolic leaf extracts of Pistia stratiotes linn in the management of arthritis and fever. J Med Biomed Sci 2012;1:29-37.
44Bendele AM, Hulman JF. Spontaneous cartilage degeneration in guinea pigs. Arthritis Rheum 1988;31:561-5.
45Huebner JL, Kraus VB. Assessment of the utility of biomarkers of osteoarthritis in the guinea pig. Osteoarthritis Cartilage 2006;14:923-30.
46Mistry D, Oue Y, Chambers MG, Kayser MV, Mason RM. Chondrocyte death during murine osteoarthritis. Osteoarthritis Cartilage 2004;12:131-41.
47Walton M. Degenerative joint disease in the mouse knee; radiological and morphological observations. J Pathol 1977;123:97-107.
48Châteauvert JM, Grynpas MD, Kessler MJ, Pritzker KP. Spontaneous osteoarthritis in rhesus macaques. II. Characterization of disease and morphometric studies. J Rheumatol 1990;17:73-83.
49Miller LM, Novatt JT, Hamerman D, Carlson CS. Alterations in mineral composition observed in osteoarthritic joints of cynomolgus monkeys. Bone 2004;35:498-506.
50Smale G, Bendele A, Horton WE Jr. Comparison of age-associated degeneration of articular cartilage in Wistar and Fischer 344 rats. Lab Anim Sci 1995;45:191-4.
51Glasson SS, Askew R, Sheppard B, Carito BA, Blanchet T, Ma HL, et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 2004;50:2547-58.
52Bendele A, McComb J, Gould T, McAbee T, Sennello G, Chlipala E, et al. Animal models of arthritis: Relevance to human disease. Toxicol Pathol 1999;27:134-42.
53Moskowitz RW, Davis W, Sammarco J, Martens M, Baker J, Mayor M, et al. Experimentally induced degenerative joint lesions following partial meniscectomy in the rabbit. Arthritis Rheum 1973;16:397-405.
54Armstrong SJ, Read RA, Ghosh P, Wilson DM. Moderate exercise exacerbates the osteoarthritic lesions produced in cartilage by meniscectomy: A morphological study. Osteoarthritis Cartilage 1993;1:89-96.
55Lindhorst E, Vail TP, Guilak F, Wang H, Setton LA, Vilim V, et al. Longitudinal characterization of synovial fluid biomarkers in the canine meniscectomy model of osteoarthritis. J Orthop Res 2000;18:269-80.
56Pond MJ, Nuki G. Experimentally-induced osteoarthritis in the dog. Ann Rheum Dis 1973;32:387-8.
57Bouchgua M, Alexander K, d'Anjou MA, Girard CA, Carmel EN, Beauchamp G, et al. Use of routine clinical multimodality imaging in a rabbit model of osteoarthritis–part I. Osteoarthritis Cartilage 2009;17:188-96.
58Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, et al. Pain related behaviour in two models of osteoarthritis in the rat knee. Pain 2004;112:83-93.
59Young RD, Vaughan-Thomas A, Wardale RJ, Duance VC. Type II collagen deposition in cruciate ligament precedes osteoarthritis in the guinea pig knee. Osteoarthritis Cartilage 2002;10:420-8.
60Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T, et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 2005;13:632-41.
61Hulth A, Lindberg L, Telhag H. Experimental osteoarthritis in rabbits. Preliminary report. Acta Orthop Scand 1970;41:522-30.
62Guingamp C, Gegout-Pottie P, Philippe L, Terlain B, Netter P, Gillet P. Mono-iodoacetate-induced experimental osteoarthritis: A dose-response study of loss of mobility, morphology, and biochemistry. Arthritis Rheum 1997;40:1670-9.
63Thakur M, Rahman W, Hobbs C, Dickenson AH, Bennett DL. Characterisation of a peripheral neuropathic component of the rat monoiodoacetate model of osteoarthritis. PloS One 2012;7:E33730.
64van Osch GJ, van der Kraan PM, Vitters EL, Blankevoort L, van den Berg WB. Induction of osteoarthritis by intra-articular injection of collagenase in mice. Strain and sex related differences. Osteoarthritis Cartilage 1993;1:171-7.
65Murat N, Karadam B, Ozkal S, Karatosun V, Gidener S. Quantification of papain-induced rat osteoarthritis in relation to time with the Mankin score. Acta Orthop Traumatol Turc 2007;41:233-7.
66Havdrup T, Telhag H. Papain-induced changes in the knee joints of adult rabbits. Acta Orthop Scand 1977;48:143-9.
67Bendele AM, Hulman JF, Harvey AK, Hrubey PS, Chandrasekhar S. Passive role of articular chondrocytes in quinolone-induced arthropathy in guinea pigs. Toxicol Pathol 1990;18:304-12.
68Ham KD, Loeser RF, Lindgren BR, Carlson CS. Effect of long-term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys. Arthritis Rheum 2002;46:1956-64.
69Bendele AM. Animal models of osteoarthritis. J Musculoskelet Neuronal Interact 2001;1:363-76.
70Schaller S, Henriksen K, Hoegh-Andersen P, Søndergaard BC, Sumer EU, Tanko LB, et al. In vitro, ex vivo, and in vivo methodological approaches for studying therapeutic targets of osteoporosis and degenerative joint diseases: How biomarkers can assist? Assay Drug Dev Technol 2005;3:553-80.
71Vasseur P. Stifle joint. Anatomy and biomechanics. Cranial cruciate ligament rupture. In: Slatter D, editor. Textbook of Small Animal Surgery. Vol. 2, 2 nd ed. Philadelphia, USA: WB Saunders; 1993. p. 1817-46.
72Trumble T, Mcllwraith C, Billinghurst R. Technique for arthroscopically guided transection of the cranial cruciate ligament as a model for osteoarthritis. The Eleventh Annual American College of Veterinary Surgeons Symposium, Chicago, Illinois; Veterinary Surgery; 2001. p. 508.
73McDevitt C, Gilbertson E, Muir H. An experimental model of osteoarthritis; early morphological and biochemical changes. J Bone Joint Surg Br 1977;59:24-35.
74De Biasi F, Rahal S, Lopes R, Volpi R, Bergamo F. Synovial fluid changes in the dog knee with osteoarthritis induced by Pond and Nuki model. Arq Bras Med Vet Zootec 2001;53:563-7.
75Otterness IG, Eskra JD, Bliven ML, Shay AK, Pelletier JP, Milici AJ. Exercise protects against articular cartilage degeneration in the hamster. Arthritis Rheum 1998;41:2068-76.
76Torelli SR, Rahal SC, Volpi RS, Sequera JL, Grassioto IQ. Histopathological evaluation of treatment with chondroitin sulphate for osteoarthritis induced by continuous immobilization in rabbits. J Vet Med A Physiol Pathol Clin Med 2005;52:45-51.
77Marijnissen AC, van Roermund PM, TeKoppele JM, Bijlsma JW, Lafeber FP. The canine 'groove' model, compared with the ACLT model of osteoarthritis. Osteoarthritis Cartilage 2002;10:145-55.
78Lahm A, Uhl M, Edlich M, Erggelet C, Haberstroh J, Kreuz PC. An experimental canine model for subchondral lesions of the knee joint. Knee 2005;12:51-5.
79Pap G, Eberhardt R, Stürmer I, Machner A, Schwarzberg H, Roessner A, et al. Development of osteoarthritis in the knee joints of Wistar rats after strenuous running exercises in a running wheel by intracranial self-stimulation. Pathol Res Pract 1998;194:41-7.
80Kim HA, Cheon EJ. Animal model of osteoarthritis. J Rheum Dis 2012;19:239-47.
81Dinser R. Animal models for arthritis. Best Pract Res Clin Rheumatol 2008;22:253-67.
82Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol 2007;213: 626-34.

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