Info

Npp1

Knockout

OA associated with crystal deposition [101]

a1-integrin

Knockout

Accelerated cartilage degradation [245]

OA pathology refers to cartilage damage and, where noted, a subchondral bone sclerosis. According to Glasson and colleagues [65,66], the severity of the OA due to surgical instability induced by destabilization of the medial meniscus depends on the wild-type strain, the 129/SvEv strain developing the most severe OA, followed by C57B10.RIIII, C57BL/6, FVB/N, and DBA. MMP-3, Cox-1, Cox-2, Jak3,

MMP-12, cPLA2a, and ADAMTS-4 KO mice displayed no exacerbation of or protection against OA pathology.

IGF, insulin-like growth factor; OA, osteoarthritis.

bony structures found at the periphery of the joint surface [196]. Regional differences may exist, however, as some studies of early OA patients show upregulation of matrix synthesis in ankle but not in knee cartilage [11]. Type X collagen, a marker of the hypertrophic chon-drocyte that is normally absent in adult articular cartilage, has been detected in certain stages in OA or in atypical sites in OA cartilage [193]. This is also true for type III and type VI collagen, which are normally present at low concentrations, and for the chondropro-genitor splice variant of the type II collagen gene, type IIA. The increase in pericellular type VI collagen microfibrils indicates that the chondrocyte can respond to changes in its microenvironment [204]. In addition to COLlOAl, which encodes type X collagen, and MMP-13, other genes associated with growth plate development, such as MMP-9 and Indian hedgehog (Ihh) occur in the vicinity of early OA lesions [219]. Surprisingly, decreased levels of Sox9 messenger RNA (mRNA), the master switch for the COL2A1-expressing chondrocyte, are detected near the lesions [219], and the expression of this factor, which is required for activation of COL2A1 transcription, does not localize with COL2A1 mRNA in adult articular cartilage [4]. Nevertheless, to enhance cartilage tissue engineering, it has been proposed to transduce Sox9 together with L-Sox5 and Sox6—both of which are required for chondrogenesis during development—into mesenchymal stem cells ex vivo or into joint tissues in vivo [97,221]. At late stages, when catabolic processes dominate, it is more difficult for the chondrocyte to replicate the complex composition of the articular cartilage matrix laid down during development. This is particularly true once there is severe damage to the collagen network. Furthermore, the chondrocyte stress response may result in the loss of viable cells due to apoptosis or senescence [5].

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