Osteoarthritis (OA) is one of the most prevalent and chronic diseases affecting the elderly. Its most prominent feature is the progressive destruction of articular cartilage, even it is now accepted that OA is a global disease involving synovial membrane, subchondral bone and periarticular soft tissues. OA may occur following traumatic injury to the joint, subsequent to an infection of the joint or simply as a result of ageing and the wear and tear associated with the stresses of daily life.
The symptoms and signs characteristic of OA in the most frequently affected joints are pain, stiffness, limited joint function, gelling tenderness, bony enlargement and malaligment. These symptoms and signs are highly variable, depending on which joint is affected and how severely it is affected.
Until a few decades ago OA was viewed as a “degenerative” or “wear-and-tear” disease which held little interest for clinicians. In fact rheumatologists refused to classify OA as one of the conditions in their own medical speciality until very recently. Veterinarians took an interest in it only because of welfare and financial reasons; they had racehorses and racing greyhounds to take care of, whose economic value to their owners and the racing industries made it a worthwhile pursuit. Thus far, human and veterinary clinical medicine has had little to offer, especially as OA was considered to be part of ageing and few distinctions were made in the clinical presentations. It is now generally accepted that OA must be viewed not only as the final common pathway for ageing and injuries of the joint but also as an active joint disease. As the population of the world grows older and medical advances lengthen average life expectancy, OA will become a larger public health problem - not only because it is a manifestation of ageing but because it usually takes many years to reach clinical relevance. OA is already one of the ten most disabling diseases in developed countries.
OA is rare in people under 40 but becomes more common with age – most people over 65 years of age show some radiographic evidence of OA in at least one or more joints. OA is the most frequent cause of physical disability among older adults globally. More than 8 million people in the UK and over 20 million Americans are estimated to have OA. It is anticipated that by the year 2030, 20% of adults will have developed OA in Western Europe and North America. OA is not only a common problem among the elderly population, but also it is becoming more widespread among younger people. In the United States, rheumatoid arthritis and OA combined affect as many as 46 million people. This amounted to a healthcare cost of over $128 billion in 2003. This huge financial burden emphasizes the acute need for new and more effective treatments for articular cartilage defects especially since there are no disease modifying drugs or treatments for OA. Existing pharmaceuticals include analgesics, steroids and non-steroidal anti inflammatory drugs which only treat the symptoms of OA by reducing pain and inflammation. Therefore OA represents a major opportunity for research and development. Any new information gained about new treatments developed for treating OA in human patients will also have benefits to companion animals such as horses and dogs which also suffer from OA.
The main chondral, subchondral and synovial events that occur in OA have been summarized in Figure 1. (adapted from a recent review by (Henrotin et al 2005b).
Please change in the picture at the subchondral bone level
Articular cartilage in OA
OA is a chronic degenerate disease with loss of articular cartilage components, particularly type-II collagen and aggrecan, as the characteristic molecular feature, because of an imbalance between extracellular matrix destruction and repair (Todhunter et al 1996). Although OA chondrocytes have increased expression of both anabolic and catabolic matrix genes (Aigner et al 2006), their catabolic ability is thought to outweigh their anabolic capacity resulting in cartilage loss. As OA progresses from mild to severe, there is a decrease in genes coding for transcription of collagen, failure to maintain the proteoglycan matrix and reduced ability of the chondrocytes to regulate apoptosis (Smith et al 2006).
OA is grossly characterized by aberrant synthesis of articular cartilage matrix, gradual hypocellularity, eventual fragmentation and degradation of articular cartilage, peri-articular new bone formation (osteophytosis), decreased, then increased, subchondral bone density and variable synovial inflammation (Buckwalter & Mankin 1998, Buckwalter et al 2000). Furthermore, OA is the clinical phenotype resulting from a number of possible abnormalities of connective tissue function combined with aberrant chondrocyte behavior and an overwhelming of the cartilage’s reparative abilities. The pathological changes observed in OA appear to follow cellular and molecular processes involving catabolic and reparative events. In OA, mechanical stress initiates cartilage lesions by altering chondrocyte-matrix interaction and metabolic responses in the chondrocytes (Goldring 2000b). There are initial increases in the amounts of water and proteoglycans associated with the observed transient chondrocyte proliferation of early OA. Proliferating chondrocytes appear in clusters or islands and are accompanied by a change in cellular organization, indicating their undifferentiated nature. In contrast collagen type X, which is normally produced by terminally differentiated hypertrophic chondrocytes, has been demonstrated surrounding chondrocyte clusters in OA cartilage (von der Mark et al 1992). Chondrocyte proliferation is considered to be an attempt to counteract cartilage degradation but disease progression and secondary inflammation proves that this is generally unsuccessful. The short-lived hyperplasia (chondrocyte cloning) is followed by hypocellularity and apoptosis (Blanco et al 1998, Blanco et al 1995, Clegg & Mobasheri 2003, Kim et al 2003, Mobasheri 2002). Catabolic events responsible for cartilage matrix degradation comprise the release of catabolic cytokines such as IL-1β, IL-6 and TNF-α (Goldring 1999, Westacott & Sharif 1996) inducing matrix degrading enzymes such as matrix metalloproteinases (MMPs), mainly stromelysine-1 (MMP-3) and collagenase-3 (MMP-13) and reactive oxygen species (ROS) by chondrocytes in early OA (Goldring 1999, Goldring 2000a, Goldring 2000b, Martel-Pelletier 1998, Westacott & Sharif 1996. Imbalance between MMPs and tissue inhibitors of MMPs (TIMPs) occurs, resulting in active MMPs and subsequently cartilage matrix degradation. However, IL-1β may also contribute to the depletion of cartilage matrix by decreasing synthesis of cartilage specific proteoglycans and collagen type II (Goldring 2000a, Richardson & Dodge 2000, Robbins et al 2000, Studer et al 1999). Beside the role played by MMPs, there is an expanded body of evidence indicating that ROS are intimately involved in the pathology of OA (Henrotin et al 2003).+ Henrotin and kurz, 2007 + Henrotin, Blanco, Aigner, Kurz, 2007) Chondrocytes are able to produce nitric oxide (●NO) and superoxide anions (O2∸), that subsequently generate derivative radicals including peroxynitrite (ONOO-), hydrogen peroxide (H2O2) and lipid peroxidation products (i.e. lipid hydroperoxides and aldehydes) (Fermor et al 2001, Henrotin et al 1993, Hiran et al 1997, Moulton et al 1998, Tiku et al 2000). IL-1b is a potent stimulator of ●NO production by chondrocytes (Henrotin Y et al, Osteoarthritis Cart 2000; Palmer RM et al. Biochem Biophys Res 1993). Some intracellular signaling pathways are redox sensitive and ROS are involved in the regulation of the production of some biochemical factors involved in cartilage degradation (I.e, MMP-13) (Sasaki K et al. J Biochem 1998) Further, ROS may cause damage to all matrix components, either by a direct attack or indirectly by reducing matrix component synthesis, by inducing apoptosis or by activating latent MMPs (Murrell GA et al. Biophys Biochem res Commun 1995; Burkhardt H et al. Arthritis Rheum 1986).
IL-1β also stimulates glucose uptake and metabolism and the secretion by chondrocytes of proinflammatory mediators, including prostaglandin E2, IL-6 and IL-8 (Hernvann et al 1996, Shikhman et al 2001). When the matrix is degraded, an inappropriate, inferior repair matrix is synthesized which cannot withstand mechanical load. Consequently, cartilage fibrillation and breakdown occurs by the focal formation of vertical, oblique and tangential clefts into the ECM and is localized preferentially in areas of proteoglycan depletion. Apoptosis is another contributing factor to the loss of articular cartilage in OA: apoptosis increases the cell loss observed in aging and OA cartilage (Adams & Horton 1998, Blanco et al 1998, Mobasheri 2002).
Synovial membrane in OA
During OA pathology, synovial membrane undergoes a moderate inflammation, which may be most pronounced immediately adjacent to the OA lesion, indicating a link between cartilage lesion and synovium inflammation (Lindblad S et al., Arthritis Rheum, 1987; Ayral X et al, Osteoarthritis cart, 2005). The inflammatory reaction is triggered by mediators released from cartilage lesion, including inflammatory cytokines (mainly IL-1b and IL-6), prostanoids (PGE2), matrix peptides (type II collagen peptide) and microcrystals (Cheung et al., front Biosc 2005). In response to these stimuli, synovial cells, including macrophages, T cells and fibroblasts, produce high levels of inflammatory cytokines (i.e.IL-1b, TNFa) (Saha, N, Arthritis Rheum, 1992; Sakkas LI, 1998), ROS, prostanoids (prostaglandins and leukotriens) and MMPs, which in turn, directly degrade cartilage or stimulate chondrocytes to secrete more MMPs and ROS resulting in an amplifying cycle and probably explaining the more rapid progression of chondropathy associated with flare episode.
Subchondral bone in OA
Although it is not yet clear whether it precedes or occurs subsequently to cartilage damage, subchondral bone remodelling is an important feature in the pathophysiology of OA and is characterized by an increase of osteoid substance deposition (sclerosis) and an abnormally low mineralization pattern (osteopenia).Thus subchondral bone stiffness is due to an increase in material density, not an increase in mineral density (Bailey AJ, Int J Biochem Cell Biol, 2002). Further, it is now well established that some osteoblasts of the OA subchondral bone are phenotypically different, and may produce increased levels of alkaline phosphatase (AP), osteoclacine, osteopontin, IL-6, IL-8, TGF-b1, IGF-1, urokinase plasminogen activator (uPA), prostaglandin (PG) E2 while levels of IGF binding proteins 3, 4 and 5 are lower and plaminogen activator inhibitor 1 and IL-1b levels remain unchanged. (Sanchez et al Arthritis Rheum 2008; Hilal G et al JBMR 2001; Hilal G Arthritis Rheum 1999 ; Massicotte F et al. Bone 2006; Hilal G et al. Arthritis Rheum 1998). Because it is a potent stimulator of bone matrix formation by osteoblasts, the local accumulation of free IGF-1 is presented as a key feature of bone sclerosis in OA. Addidionally, OA osteoblasts are resistant to parathyroid hormone (PTH) stimulation, a situation that can also contribute to abnormal bone remodelling and bone sclerosis in OA. OA osteoblasts produce an abnormal homotrimeric type I collagen with a low affinity for calcium, responsible for the low mineralization of collagen matrix of OA subchondral bone. These findings suggest that abnormal osteoblasts play a critical role in subchondral bone sclerosis. Conversely, IL-6, PGE2 and RANKLmay also be responsible for the increase number of active osteoblasts found in OA subchondral bone and bone resorption observed in the early phase of experimental OA (Jones DH, Ann Rheum Dis, 2002). Other forms of remodelling also occur in the subchondral bone, either benath the weight bearing surface of at the margins of the joints. The latter constitute the osteophytes so characteristic of primary OA. Two other characteristics of OA subchondral bone are microfracture and pseudocysts, which also have a potential role in the progression of osteoarthritis (Sokoloff L Arch Pathol Lab Med 1993).
Subchondral bone/cartilage crosstalk
Osteoblasts secrete a number of biochemical factors that are involved in the remodeling of bone tissue, and these could also contribute to remodeling of the overlying cartilage in weight bearing joints after seeping through microcracks in the calcified layer of articular cartilage. Three elements support this hypothesis : (1) microcraks have been identified bone/cartilage junction allowing exchange between the two tissues (Sokoloff L, Arch Pathol Lab Med, 1993); (2) hepatocyte growth factor), which is secreted by osteoblasrs but not by chondrocytes, are detected in the deep layers of OA cartilage (Reboul P,Arthritis Rheum, 2001), (3) Westacott et al have shown that that conditioned media from primary osteoblasts od OA patients versus subjects without arthritis significantly altered glycosaminoglycan release from normal cartilage in vitro, while cytokine release from these cells remain intact. Taking all these observations into consideration, our laboratory has proposed the following hypothesis (Figure 2). OA - altered subchondral osteoblasts may contribute to the degradation of overlying cartilage through the seeping of biochemical factors. To verify this hypothesis, we have developed an original co-culture model, in which subchondral osteoblasts in monolayer are cultured together with OA chondrocytes in alginate beads. By this wqay, we have demonstrated that osteoblasts from sclerotic (SC) zones of subchondral OA, but not non-sclerotic (N) osteoblasts, downregulated aggrecan synthesis and upregulated metalloproteases expression by chondrocytes in this co-culture model. (references). Further, microfractures of the bone plate allow vascularisation of the cartilage, a phenomenum which could contribute to hypertrophic differentiation of chondrocytes and cartilage matrix mineralization.
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