Mediators of Cartilage Homeostasis

A number of proteins that mediate normal cellular responses to stress, inflammation, and aging have been identified in OA cartilage. Findings that catabolic stress and inflammatory cytokines upregulate HIF-1a suggest that this molecule may serve as a survival factor in OA cartilage [41,133,244]. VEGF and its receptors are expressed in OA cartilage, and the induction of VEGF in chondrocytes or synovial cells by cytokines or mechanical loading indicates that VEGF may play a role in angiogenesis and cartilage destruction [84,92,176]. Recent evidence indicates that peroxisome proliferator-activated receptor 7 (PPAR7) agonists protect chondrocytes against IL-1-induced responses by increasing the expression oftheIL-1Ra [61]. The human cartilage glycoprotein 39 (HC-gp39), also known as chitinase 3-like protein 1 (Chi3L1), is induced by inflammatory cytokines and inhibits cytokine-induced cellular responses, thus constituting a feedback mechanism [120,180]. The accumulation of advanced glycation end products (AGEs) in aging cartilage suggests that chondrocyte function maybe modulated by changes in the composition/content of the extracellular matrix. The receptor for AGEs (RAGE) in chondrocytes interacts preferentially with S100A4, a member of the S100 family of calcium-binding proteins, and stimulates MMP-13 production via phosphorylation of Pyk2, MAP kinases, and NF-kB [239]. The fibroblast activation protein a (FAPa), a membrane serine proteinase, which is induced by IL-1 and OSM chondrocytes and is elevated in OA, may play a role in collagen degradation [146]. The elevated expression of leptin in OA cartilage and in osteophytes and the capacity of this adipocytokine to stimulate IGF-1 and TGF-^1 synthesis suggest that it may play a regulatory role in anabolic responses by OA chondrocytes [49]. Members ofthe CCNgene family, including connective tissue growth factor (CTGF) and NOV/CCN3, and WISP-3/CCN6 enhance BMP and TGF-^ signaling and increase Sox9-dependent COL2A1 and aggrecan expression [98,112,199]. Together the genes mentioned above seem to play key roles in regulating cartilage matrix homeostasis.

3.6 Factors in Subchondral Bone that May Contribute to Dysfunctional Chondrocyte Responses in Osteoarthritis

As proposed originally by Radin and Rose [179], bone is intimately involved in the initiation and progression of OA, and trauma to the subchondral bone may result in cartilage degeneration [32,33,152; cf. chapter 2]. Increased trabecular bone volume with trabec-ular sclerosis and increased bone turnover are features of OA pathogenesis. Therefore, therapies that target bone may also be effective in OA. Examples are calcitonin [12,50], bisphosphonates [205], and estrogen [83]. The mechanism of their action may involve subchondral osteoblasts. In a coculture model, osteoblasts isolated from sclerotic subchon-dral bone stimulate MMP-3 and MMP-13 gene expression and inhibit aggrecan synthesis. These responses are mimicked in nonscle-rotic osteoblasts treated with IL-1, IL-6, or OSM [192]. IL-17 is a potent inducer of receptor activation of NF-kB ligand (RANKL), which mediates osteoclast differentiation and activity [131]. Both RANKL and its receptor RANK, a member of the tumor necrosis factor receptor family, are expressed in adult articular chondrocytes, but exogenous RANKL does not activate NF-kB or stimulate the production of collagenase or nitric oxide [109]. However, inhibition of RANKL expression does not block cartilage destruction inflammatory models [169]. Conceivably, RANKL may have indirect effects on cartilage by its protective effect on bone [246].

It is as yet unclear whether OA is the result of changes in subchondral bone [13; cf. chapter 2], but changes in the mineral content and thickness of the calcified cartilage and the associated advancement of the tidemark may play a greater role than previously realized [33] (Fig. 3.1). Recent studies in OA patients have identified polymorphisms in the gene that encodes asporin. Asporin binds to TGF-P, thereby inhibiting cartilage anabolism. Polymorphisms have also been identified in FRZB, a gene that encodes secreted frizzled-related protein 3 (sFRP3) [113,129] (Table 3.2). These observations lend support to the concept of increased biologic activity in subchondral bone. Members of the sFRP family, including sFRP3, are glycoproteins that antagonize the signaling of Wnt ligands through frizzled membrane-bound receptors. In OA cartilage, sFRP may have a role in chondrocyte apoptosis [100]. Since activation of P-catenin in mature cartilage cells stimulates hypertrophy, matrix mineralization, and expression of VEGF, ADAMTS5, MMP-13, and of several other MMPs [214], defective inhibition of Wnt signaling due to FRZB polymorphisms may disrupt normal function, leading to abnormal cartilage and bone metabolism.

The localization of COL10A1, MMP-13, and Runx2 in the deep zone of OA cartilage suggests that the chondrocytes attempt a defective repair response by recapitulation of the hypertrophic phenotype [3,231]. In the developing growth plate, Runx2-dependent expression of RANKL is observed in the hypertrophic chondrocytes that are at the boundary, next to the calcifying cartilage [107]. This suggests that cells in bone and calcified cartilage interact. The growth arrest and DNA inducible protein, GADD457, which mediates cell survival and the expression of Mmp13 and Col10a1 in hyper-trophic chondrocytes in the growth plate, may also be a target in OA cartilage, where it is expressed in chondrocytes, in clusters and in deep zone OA chondrocytes [96]. An imbalance between IGF and IGFBP and the presence of the hepatocyte growth factor may modulate cartilage calcification, affecting interactions between deep zone chondrocyte and the subchondral bone [81,135].

The disruption of cartilage and bone formation during embryonic development also suggests that interactions between these tissues are important for the development of OA (Table 3.1). After birth, mutations in signaling proteins involved in chondrogenesis and in terminal chondrocyte differentiation may enhance susceptibility to OA. Mutation in the Ank gene encoding a multipass transmembrane protein and knockout of nucleotide pyrophos-phatase phosphodiesterase-1 (Nnp1), whose gene products control intracellular pyrophosphate levels, cause progressive or early-onset OA, associated with increased chondrocyte hypertrophy and inappropriate mineralization of the cartilage matrix [89,101]. Disruption of BMP signaling by ablation of the Bmpr1a gene, which encodes the type I BMP receptor a, results in early embryonic death, but a postnatal conditional knockout results in OA-like cartilage degeneration [184]. Loss of TGF-P signaling also increases OA-like pathology in postnatal articular cartilage, associated with increased chondrocyte hypertrophy and expression of Col10a1 [200,240].

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