OSTEOARTHRITIS AS AN ORGAN DISEASE
Peter Muir BVSc, MVetClinStud, PhD, DACVS, DECVS
University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI, USA
Osteoarthritis (OA) essentially represents failure of an organ, the synovial joint. As OA
develops, all of the joint structures are affected including articular cartilage, calcified cartilage,
subchondral cortical and trabecular bone, joint capsule, and synovium (Goldring & Goldring
2010). OA is hard to precisely define, but is considered to result from mechanical and biologic
events that destabilize the normal coupling of degradation and synthesis of articular cartilage
chondrocytes, extracellular matrix (ECM), and subchondral bone. OA may be initiated by
multiple factors, including genetic, congenital, developmental, metabolic factors, and trauma. In
general, a key feature of OA pathogenesis is excessive joint loading.
Insight into the pathogenesis of OA has improved as knowledge of the tissue composition
and structure of cartilage and subchondral bone and the molecular pathways that regulate
cartilage and bone metabolism has advanced. The relative contributions of cartilage and bone
adaptation to development of OA have not been precisely established, but both are important.
Experimental studies in animal models have been important for defining time-dependent changes
in cartilage and bone during OA initiation and progression, as well as defining genetic factors
that impact OA pathogenesis.
An emerging idea is that the syndrome of OA really consists of a number of different
disease sub-types that are stratified by various factors such as the degree of pathology in the
different tissues that make up the joint, the rate of progression of disease over time, the severity
of clinical signs, and the initiating cause(s), patient gender and age (Driban et al. 2010).
Therefore OA may be early-, late-, post-traumatic-, age-related-, inflammatory-, cartilageerosive-, osteophytic-, etc (Little & Zaki 2012).
Articular cartilage
The interterritorial matrix of hyaline cartilage is composed of a fibrillar collagen network
that contains the large proteoglycan aggrecan, as well as several other molecules. Collagen
fibers largely consist of type II collagen fibrils, with type XI and IX collagen within and on the
fibril surface respectively. These minor collagens allow association with other matrix
components and retention of proteoglycans. In addition, the pericellular matrix contains type VI
collagen microfibrils. Hyaline cartilage is organized into distinct zones from superficial to deep,
in which chondrocytes and matrix constituents vary. Chondrocytes in the superficial zone
express lubricin, which is essential for boundary lubrication of the joint surface. Chondrocytes
are habitually exposed to low oxygen tension and consequently express hypoxia-inducible
factor-alpha (HIF-1α). HIF-1α is an important regulator of genes associated with cartilage
anabolism and catabolism, such as vascular endothelial growth factor (VEGF) and SOX9. With
aging, chondrocyte stress is increased and characteristic matrix changes develop, including
accumulation of advanced glycation end products (AGEs), which enhance collagen crosslinking.
During OA initiation and progression, deterioration in the molecular composition and
structural integrity of hyaline cartilage occurs. Chondrocytes can respond to mechanical forces,
structural changes in the pericellular matrix, as well as intrinsic and extrinsic molecular signals.
With development of OA, cellular proliferation leads to chondrocyte clustering and synthesis of
specific matrix components is increased. As OA progresses, increased cartilage catabolism
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develops, with gradual loss of proteoglycans and eventual loss of type II collagen. Important
catabolic enzymes include matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, MMP-13, and
MMP-14, as well as the aggrecanases ADAMTS4, ADAMTS5, and ADAMST9 [a disintegrin
and metalloproteinase with thrombospondin-like motifs]. Changes to chondrocytes during OA
development include increased expression of regulatory proteins (IL-1, TNF-α, toll-like
receptors [TLRs]), matrix proteins (collagen type II and X, aggrecan, link protein, osteopontin),
stress and apoptotic markers (caspases 3 and 9, Bcl-2) and transcription factors (SOX9,
RUNX2). These changes to chondrocytes are associated with fibrillation of the cartilage surface
and production of fibrocartilage.
Calcified cartilage and tidemark advancement
The tidemark represents the demarcation line between hyaline articular cartilage and
calcified cartilage. Widening of the zone of calcified cartilage as well as advancement of the
tidemark and the presence of multiple tidemarks are commonly found in OA joints. Targeted
remodeling of joint microcracks from mechanical injury is likely important factor leading to
these changes (Burr 2004, Muir et al. 2006). Vascular ingrowth from epiphyseal bone into the
tidemark is associated with up-regulation of nerve growth factor and sensory nerve fiber
sprouting, suggesting a link between osteochondral angiogenesis and joint pain (Walsh et al.
2010). With tidemark advancement, there is associated thinning of articular cartilage, as well as
increasing mechanical stress on the deep zones of hyaline articular cartilage.
Subchondral bone
Periarticular bone consists of the subchondral plate, as well as subchondral trabecular
bone and bone at the joint margins (Goldring & Goldring 2010). The subchondral plate consists
of compact cortical bone that is separated from hyaline articular cartilage by calcified cartilage.
Functional adaptation of periarticular bone will occur in response to joint loading events through
modeling and remodeling. In general, modeling involves addition of new bone onto existing
bone surfaces, whereas remodeling involves osteoclast activation on quiescent surfaces and
removal of bone packets, followed by formation of new bone. Bone removal and formation are
normally in balance. In addition, the quality of periarticular bone may be influenced by matrix
mineralization. If bone turnover is low, hypermineralization may develop and lead to an increase
in bone modulus. Conversely, poor mineralized may lead to a decrease in bone modulus (Burr
2004).
During development of OA, thickening of the subchondral plate develops together with
modeling of subchondral trabecular bone, and formation of new bone formation at joint margins
(osteophytes). In the late phase of OA, subchondral cysts may be found. Vascular invasion of
the tidemark is associated with these bony changes (Muir et al. 2006, Walsh et al. 2007).
Changes to subchondral bone are often associated with alteration to the contour of the overlying
joint surface (Burr 2004). Adaptive change to periarticular bone begins very early in the
initiation of OA.
Considerable controversy exists regarding the effects of subchondral bone adaptation to
loading on adjacent hyaline cartilage. It has been hypothesized that adaptive enlargement of the
thickness of the subchondral bone plate will lead to increased stiffness and associated adverse
effects on the biomechanical environment of overlying cartilage (Radin & Rose 1986, BucklandWright 2004). Although subchondral bone volume is increased with OA, recent work has
suggested that bone tissue modulus may actually be decreased, principally because of rapid bone
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turnover, reduced bone volume and trabecular thickness, and reduced tissue mineralization (Day
et al. 2001, Boyd et al. 2002, Buckland-Wright 2004). Such observations have important
implications for OA treatment, particularly through use of drugs that may modulate bone
remodeling.
With the wider use of MRI imaging in both humans and animals, the presence of discrete
areas of increased signal intensity using fluid-sensitive MRI sequences has been found in
subchondral bone in various OA conditions. This phenomenon was recently described in dogs
with stifle arthritis associated with non-contact cruciate rupture (Winegardner et al. 2007). The
presence of these lesions correlates with joint pain (Taljanovic et al. 2008). These lesions are
associated with the presence of trabecular microfractures, fibrous replacement of bone marrow,
and increased bone remodeling histologically (Taljanovic et al. 2008).
Formation of osteophytes at the joint margins is another key feature of OA joint
degeneration. Osteophyte initiation is associated with proliferation of periosteal cells,
differentiation into chondrocytes, and formation of a bony osteophyte through endochondral
ossification. Local production of growth factors, such as transforming growth factor beta (TGFβ) and bone morphogenetic proteins (BMPs) is important for regulation of osteophyte formation
(Blaney Davidson et al. 2007).
Inflammation and joint damage
In the past, OA has been considered to be a joint disease with little or no inflammatory
component. However, synovitis is also common in patients affected with OA and typically
exhibits features of a T lymphocyte immune response (Sakkas & Platsoucas 2007). These
findings strongly suggest that the traditional view in both human and veterinary medicine that
OA is a non-inflammatory disease must be reconsidered. OA should be considered an
inflammatory condition. There are also distinct differences in synovial fluid cytokine expression
between early- and late-OA. Up-regulation of IL-15 is a distinct feature of early OA, together
with increased numbers of CD8+ T lymphocytes (Scanzello et al. 2007). IL-15 has a central role
as an early mediator of immune responses and is principally activated through TLR signaling,
particularly TLR-2 and -4 (Jung et al. 2007, Ling et al. 2009). Systemic changes to the
musculoskeletal system can also be found in patients with OA (Ling et al. 2009). A unique
serum protein signature precedes development of radiographic arthritis, suggesting that altered
extracellular matrix metabolism plays a key role in the initiation of OA (Ling et al. 2009).
White adiopose tissue has also been proposed as a major source of both pro- and antiinflammatory cytokines, including interleukin-1 receptor antagonist (IL-1RA) and IL-10 (Dayer
et al. 2006). Expression of leptin is also elevated in OA cartilage and osteophytes and stimulates
IGF-1 and TGF-β synthesis in chondrocytes (Dumond et al. 2003). Dysregulation of the balance
in signaling between leptin and other adipokines, such as adiponectin and resistin, may promote
destructive joint inflammation in OA (Gomez et al. 2009).
Genetics
This is a rapidly evolving field. Results of epidemiological and familial studies, as well
as analysis of rare genetic disorders, suggest that genetic mutations are an important factor in the
risk of early-onset OA. Candidate gene and genome-wide association studies (GWAS) have
implicated mutations in genes encoding ECM proteins and signaling molecules. Molecules of
interest include fibroblast growth factor (FGF), TGF-β, BMPs, and components of the Wnt
signaling pathway that regulates chondrocyte differentiation and maturation during skeletal
development. It remains unclear to what extent genetic risk contributes to general OA
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susceptibility in both animals and human beings. However, GWAS of dogs and human beings
have discovered significant SNP associations with completely novel genetic risk factors (Zhou et
al. 2010, Castano Betancourt et al. 2012).
Effects of mechanical loading of joints
OA often arises secondary to impact loading from serious joint injury. However, minor
damage from habitual loading of joints is also an important causative factor in OA pathogenesis.
The manner in which physiologically reasonable loads are applied to joints is critical to joint
health. Loads that are applied too rapidly overwhelm viscoelastic shock absorption and lead to
microdamage to cartilage and subchondral bone. In this regard, muscles provide the majority of
impact absorption during joint loading. Therefore, muscle fatigue can be an important factor
leading to joint damage in running athletes. As joint microdamage accumulates, reactivation of
endochondral ossification occurs as a reparative mechanism. Over time, habitual loading that
leads to joint damage will induce thickening of the subchondral plate, thinning of articular
cartilage, and eventual loss of cartilage. Experimentally, vertical fibrillations in articular
cartilage may not progress, as long as the laceration does not cross the tidemark into subchondral
bone (Meachim 1963).
References
 Blaney Davidson EN, van der Kraan PM, van den Berg WB. TGF-β and osteoarthritis.
Osteoarthr Cartil 2007;15:597-604.
 Boyd SK, Muller R, Zernicke RF. Mechanical and architectural bone adaptation in early
stage experimental osteoarthritis. J Bone Miner Res 2002;17:687-694.
 Buckland-Wright C. Subchondral bone changes in hand and knee osteoarthritis detected
by radiography. Osteoarthr Cartil 2004;12:S10-19.
 Burr DB. Anatomy and physiology of the mineralized tissues: Role in the pathogenesis
of osteoarthrosis. Osteoarthr Cartil 2004;12:S20-S30.
 Castano Betancourt MC, Cailotto F, Kerkhof HJ, et al. Genome-wide association and
functional studies identify the DOT1L gene to be involved in cartilage thickness and hip
osteoarthritis. PNAS 2012, epub.
 Day JS, Ding M, van der Linden JC, et al. A decreased subchondral trabecular bone
tissue elastic modulus is associated with pre-arthritic cartilage damage. J Orthop Res
2001;19:914-918.
 Dayer J-M, Chicheportiche R, Juge-Aubry C, Meier C. Adipose tissue has antiinflammatory properties. Focus in IL-1 receptor antagonist (IL-1Ra). Ann N Y Acad Sci
2006;1069:444-453.
 Driban JB, Sitler MR, Barbe MF, Balasubramanian E. Is osteoarthritis a heterogenous
disease that can be stratified into subsets? Clin Rheumatol 2010;29:123-131.
 Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis.
Arthritis Rheum 2003;48:3118-3129.
 Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis
of osteoarthritis. Ann N Y Acad Sci 2010;1192:230-237.
 Gomez R, Lago F, Gomez-Reino J, et al. Adipokines in the skeleton: influence on
cartilage function and joint degenerative diseases. J Mol Endocrinol 2009;43:11-18.
570
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Jung YO, Cho M-L, Kang C-M, et al. Toll-like receptor 2 and 4 combination
engagement upregulate IL-15 synergistically in human rheumatoid arthritis synovial
fibroblasts. Osteoarthr Cartil 2007;109:21-27.
Ling SM, Patel DD, Garnero P, et al. Serum protein signatures detect early radiographic
osteoarthritis. Osteoarthr Cartil 2009;17:43-48.
Little CB, Zaki, S. What constitutes an “animal model of osteoarthritis” – the need for
consensus? Osteoarthr Cartil 2012;20:261-267.
Meachim G. The effect of scarification on articular cartilage in the rabbit. J Bone Joint
Surg 1963:45B:150-161.
Muir P, McCarthy J, Radtke CL, et al. Role of endochondral ossification of articular
cartilage and functional adaptation of the subchondral plate in the development of fatigue
microcracking of joints. Bone 2006;38:42-49.
Radin EL, Rose RM. Role of subchondral bone in the initiation and progression of
cartilage damage. Clin Orthop Rel Res 1986;213:34-40.
Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis.
Arthritis Rheum 2007;56:409-424.
Scanzello CR, Umoh E, Pessler F, et al. Local cytokine profiles in knee osteoarthritis:
elevated synovial fluid interleukin-15 differentiates early from end-stage disease.
Osteoarthr Cartil 2009;17:1040-1048.
Taljanovic MS, Graham AR, Benjamin JB, et al. Bone marrow edema pattern in
advanced hip osteoarthritis: quantitative assessment with magnetic resonance imaging
and correlation with clinical examination, radiographic findings, and histopathology.
Skeletal Radiol 2008;37:423-431.
Walsh DA, Bonnet CS, Turner EL, et al. Angiogenesis in the synovium and at the
osteochondral junction in osteoarthritis. Osteoarthr Cartil 2007;15:743-751.
Walsh DA, McWilliams DF, Turley MJ, et al. Angiogenesis and nerve growth factor at
the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology
2010;49:1852-1861.
Winegardner KR, Scrivani PV, Krotscheck U, Todhunter RJ. Magnetic resonance
imaging of subarticualar bone marrow lesions in dogs with stifle lameness. Vet Radiol
Ultrasound 2007;48:312-317.
Zhou Z, Sheng X, Zhang Z, et al. Differential genetic regulation of canine hip dysplasia
and osteoarthritis. PLoS One 2010;5;e13219.
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