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Matrix remodeling during enchondral ossification and aggrecan cleavage in osteoarthritic cartilage depends on syndecan-4

Chondrocyte differentiation into hypertrophic chondrocytes is essential for enchondral ossification of long bones during limb development, but plays a role also in pathologic situations such as osteoarthritis (OA). However, the mechanisms that link chondrocyte hypertrophy to cartilage remodeling are poorly understood. Based on recent data that have implicated transmembrane heparan sulfate proteoglycans in matrix turnover and cell differentiation, we analyzed the role of syndecan-4 during limb development in mice and studied its expression and function in OA.

Syndecan-4 promoter activity was detected in whole embryos by staining for β-galactosidase in syndecan-4-/- LacZ knockin mice. For cellular localization of syndecan-4 expression within cartilage, immunohistochemistry with antibodies against syndecan-4 and type X collagen was performed. Alizarin red S staining was carried out to analyze the mineralization of bones in wild-type and syndecan-4-/- littermates at days E13.5 and E14.5. To study syndecan-4 in OA, we compared its expression in normal and OA articular cartilage by Northern blot analysis and immunohistochemistry. Blocking antibodies against syndecan-4 were generated and used to analyze the role of syndecan-4 in IL-1-mediated proteoglycan loss in vitro. For functional analysis in vivo, osteoarthritic changes were induced in syndecan-4-/- mice and in wild-type controls by surgically achieved joint instability, and the loss of proteoglycans was assessed by safranin-orange staining. Staining for syndecan-4 and ADAMTS-generated aggrecan neo-epitopes was performed in the knees of these mice.

β-Galactosidase-staining of syndecan-4-/- mice at E12.0 showed a strong activity of the syndecan-4 promoter at sites of cartilage condensations. In later stages, syndecan-4 was detected in the growth plates of long bones. In wild-type embryos, syndecan-4 protein was also found mainly in chondrocytes of the hypertrophic zone, where it colocalized with type X collagen. The loss of syndecan-4 was associated with a significant retardation in the mineralization of axial and appendicular bones. Interestingly, there was a clear upregulation of syndecan-4 in human OA cartilage both at the mRNA and the protein level. In the cartilage explant model, blocking antibodies to syndecan-4 substantially significantly reduced the IL-1-induced loss of proteoglycans in wild-type cartilage. Analysis of OA-like changes in mice revealed a strong and early induction of syndecan-4, and there was a significant reduction of proteoglycan loss in the syndecan-4-/- mice compared with their wild-type controls. This was accompanied by a significantly reduced staining for ADAMTS-generated aggrecan neo-epitopes in syndecan-4-/- mice.

Our data show that syndecan-4 is induced in hypertrophic chondrocytes both during embryogenesis and in OA cartilage. By promoting ADAMTS-mediated cleavage of aggrecans, syndecan-4 facilitates enchondral ossification but is involved also in cartilage degradation by hypertrophic chondrocytes in OA. Inhibition of syndecan-4 may therefore constitute a promising strategy to interfere with osteoarthritic cartilage damage.

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Echtermeyer, F., Neugebauer, K., Meinecke, I. et al. Matrix remodeling during enchondral ossification and aggrecan cleavage in osteoarthritic cartilage depends on syndecan-4. Arthritis Res Ther 9 (Suppl 3), P38 (2007).

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