7, 8 Syndecans positively or negatively modulate Wnt signaling. Syndecans also interact with high-affinity receptors and integrins to modulate intracellular signaling. They are low-affinity co-receptors with roles in docking, protection and concentration of their ligands. Syndecans are cell-surface heparan sulfate proteoglycans (HSPGs). Indeed, in addition to sclerostin activity, that of Wnt proteins and many other Wnt modulators also depends on interactions with proteoglycans. 5 Thus, a key function of GAGs in fostering osteogenesis may involve modulating Wnt signaling. Recently, sulfated hyaluronan and chondroitin sulfate were reported to inhibit sclerostin and to enhance bone regeneration in diabetic rats. GAGs at the surface of osteoblastic cells could be major factors in the bone surface environment. Moreover, GAGs are unique to each cell type because they depend on the assembly machinery and modifying enzymes and the expression pattern of the proteoglycans. To design more optimal GAGs for clinical use in bone regeneration, we need to better understand the functions of endogenous cellular GAGs. In the various studies, only soluble or matrix-associated GAGs were considered. 1, 2 Moreover, GAG accumulation was shown to have a role in the bone diseases associated with mucoplysaccharidoses or Leri pleonosteosis. Synthetic sulfated GAGs showed osteogenic properties in vitro and were proposed to be useful for biomaterial coating however, contrasting results were obtained and the effects of GAGs on bone formation and resorption are still unclear. Glycosaminoglycans (GAGs) are key component of the bone matrix and cell surface that modulate the bioavailability and activity of various osteoclastic and osteogenic factors. Improving bone formation is an important issue to rescue bone loss in aging patients or to repair bone defects after fracture or tumor resection. In conclusion, our results show that GAG supply may improve osteogenesis, but also interfere with the crosstalk between the bone surface and marrow cells, altering the supporting function of osteoblasts. Finally, syndecan-2 functions as an inhibitor of Wnt-β-catenin–T-cell factor signaling pathway, activating glycogen synthase kinase 3 and then decreasing the Wnt-dependent production of Wnt ligands and R-spondin. However, syndecan-2 specifically promoted the vasculature characterized by high expression of CD31 and Endomucin in 6-week-old transgenic mice, but this was reduced in 12-week-old transgenic mice. Indeed, syndecan-2 overexpression increased apoptosis of mesenchymal precursors within the bone marrow. Increased proteoglycan expression at the bone surface resulted in decreased osteoblastic and osteoclastic precursors in bone marrow. Osteoblast activity was not modified in the transgenic mice, but bone formation was decreased in 4-month-old transgenic mice because of reduced osteoblast number. Syndecan-2 overexpression reduced the expression of receptor activator of NF- kB ligand (RANKL) in bone marrow cells and strongly inhibited bone resorption. Bone mass was increased in these transgenic mice. We used a transgenic mouse model with high syndecan-2 expression in osteoblasts to enrich the bone surface with cellular GAGs. Syndecan-2 is a membrane heparan sulfate proteoglycan that is associated with osteoblastic differentiation. The osteogenic properties of matrix glycosaminoglycans (GAGs) have been explored however, the functions of GAGs at the surface of bone-forming cells are less documented. Stimulating bone formation is an important challenge for bone anabolism in osteoporotic patients or to repair bone defects.
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