Syndecan-3 Is a Selective Regulator of Chondrocyte Proliferation

Abstract

Chondrocyte proliferation is important for skeletal development and growth, but the mechanisms regulating it are not completely clear. Previously, we showed that syndecan-3, a cell surface heparan sulfate proteoglycan, is expressed by proliferating chondrocytes in vivo and that proliferation of cultured chondrocytes in vitro is sensitive to heparitinase treatment. To further establish the link between syndecan-3 and chondrocyte proliferation, additional studies were carried out in vivo and in vitro. We found that the topographical location of proliferating chondrocytes in developing chick long bones changes with increasing embryonic age and that syndecan-3 gene expression changes in a comparable manner. For in vitro analysis, mitotically quiescent chondrocytes were exposed to increasing amounts of fibroblast growth factor-2 (FGF-2). Proliferation was stimulated by as much as 8 -10-fold within 24 h; strikingly, this stimulation was significantly prevented when the cells were treated with both fibroblast growth factor-2 (FGF-2) and antibodies against syndecan-3 core protein. This neutralizing effect was dose-dependent and elicited a maximum of 50 -60% inhibition. To establish specificity of neutralizing effect, cultured chondrocytes were exposed to FGF-2, insulin-like growth factor-1, or parathyroid hormone, all known mitogens for chondrocytes. The syndecan-3 antibodies interfered only with FGF-2 mitogenic action, but not that of insulin-like growth factor-1 or parathyroid hormone. Protein cross-linking experiments indicated that syndecan-3 is present in monomeric, dimeric, and oligomeric forms on the chondrocyte surface. In addition, molecular modeling indicated that contiguous syndecan-3 molecules might form stable complexes by parallel pairing of ␤-sheet segments within the ectodomain of the core protein. In conclusion, the results suggest that syndecan-3 is a direct and selective regulator of the mitotic behavior of chondrocytes and its role may involve formation of dimeric/oligomeric structures on their cell surface.Chondrocytes constitute the embryonic cartilaginous skeleton, the growth plates of fetal and postnatal skeletal elements, and permanent cartilages such as articular cartilage, nasal septum, and tracheal rings. In these various structures and locations, chondrocytes exhibit characteristic and strictly controlled mitotic activity, and this activity has diverse roles and implications. For example, in the growth plate chondrocyte proliferation is topographically limited to a narrow zone flanked by a resting zone of quiescent cells and an underlying zone of postmitotic prehypertrophic cells (1). A main role for chondrocyte proliferation in the growth plate is to counterbalance the loss of hypertrophic chondrocytes occurring at the chondro-osseous border and their replacement by endochondral bone cells. A second important role is to determine the overall rates of skeletal growth, as illustrated by the different rates of proliferation displayed by chondrocytes in long bones elongating at different rates ...

Induction of a CXCL8 binding site on endothelial syndecan‐3 in rheumatoid synovium

“…Interestingly, it is also an HSPG in the musculoskeletal system. The results of our study in adult human joints show that syndecan-3 is expressed in RA and nonrheumatoid synovium; it is also expressed by chondrocytes in normal and OA articular cartilage, and it is a regulator of chondrocyte proliferation (50,62). Furthermore, syndecan-3 is involved in limb morphogenesis and skeletal development, including chondrogenesis and joint formation, and skeletal muscle regeneration (63,64).…”

Indian hedgehog and syndecans‐3 coregulate chondrocyte proliferation and function during chick limb skeletogenesis

“…Figure 3 shows the results of day 7 embryos in which radius (r) and ulna (u) had been infected. In control embryos, syndecan-3 gene expression and proliferating chondrocytes exhibited predictable patterns and location at that stage (Koyama et al, 1995;Kirsch et al, 2002) and were both restricted to the epiphyseal ends ( Fig. 3A,C,E, arrows).…”

“…Effects of heparinase I were dose-dependent and maximal at 1 U/ml (not shown). Next, cultures were treated with rIhh-N in the presence of syndecan-3 neutralizing antibodies (Kirsch et al, 2002). Antibody treatment counteracted the stimulatory effects of rIhh-N on proliferation in both uninfected and syndecan-3-overexpressing cultures (Fig.…”

“…5B, arrowhead) which no longer occupied the epiphyseal end at this stage but was now located in the metaphysis below the articular cap ( Fig. 5B, ac; Shimazu et al, 1996;Kirsch et al, 2002). Ihh gene expression was also strong and restricted to the prehypertrophic zone (Fig.…”

“…The known four members are differentially expressed and regulate several developmental events and processes in which they act as receptors and coreceptors for factors, cytokines or matrix components such as fibronectin (Bernfield et al, 1999;Iozzo, 2001). We previously showed that syndecan-3 gene expression and distribution are restricted to the proliferative zone of the growth plate (Koyama et al, 1995;Shimazu et al, 1996;Kirsch et al, 2002), raising the possibility that syndecan-3 may participate in Ihh function in that zone and allow the factor to directly influence chondrocyte proliferation. The results presented here provide support for this possibility and are the first to identify a specific member of the syndecan family in hedgehog action.…”