Abstract
Stimulating bone formation is an important challenge for bone anabolism in osteoporotic patients or to repair bone defects. 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. Syndecan-2 is a membrane heparan sulfate proteoglycan that is associated with osteoblastic differentiation. We used a transgenic mouse model with high syndecan-2 expression in osteoblasts to enrich the bone surface with cellular GAGs. Bone mass was increased in these transgenic mice. Syndecan-2 overexpression reduced the expression of receptor activator of NF-kB ligand (RANKL) in bone marrow cells and strongly inhibited bone resorption. 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. Increased proteoglycan expression at the bone surface resulted in decreased osteoblastic and osteoclastic precursors in bone marrow. Indeed, syndecan-2 overexpression increased apoptosis of mesenchymal precursors within the bone marrow. 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. 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. 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.
Highlights
Improving bone formation is an important issue to rescue bone loss in aging patients or to repair bone defects after fracture or tumor resection
Syndecan-2 was detected in bone marrow cells (BMCs), osteoblasts and osteocytes In wild-type (WT) mice (Figure 1a)
The osteoblasts (CD51+Sca-1− cells) in the marrow of transgenic mice had a significant increase in syndecan-2 levels as compared to osteoblasts from WT mice (Figure 1c)
Summary
Improving bone formation is an important issue to rescue bone loss in aging patients or to repair bone defects after fracture or tumor resection. Glycosaminoglycans (GAGs) are key component of the bone matrix and cell surface that modulate the bioavailability and activity of various osteoclastic and osteogenic factors. Synthetic sulfated GAGs showed osteogenic properties in vitro and were proposed to be useful for biomaterial coating; contrasting results were obtained and the effects of GAGs on bone formation and resorption are still unclear.[1,2] GAG accumulation was shown to have a role in the bone diseases associated with mucoplysaccharidoses or Leri pleonosteosis.[3,4]. Sulfated hyaluronan and chondroitin sulfate were reported to inhibit sclerostin and to enhance bone regeneration in diabetic rats.[5] a key function of GAGs in fostering osteogenesis may involve modulating Wnt signaling. Syndecans are cell-surface heparan sulfate proteoglycans (HSPGs). They are low-affinity co-receptors with roles in docking, protection and concentration of their ligands
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