Abstract
Syndecans, a family of cell surface heparan sulfate proteoglycans, regulate cell differentiation via binding of their heparan sulfate chains to growth factors and cytokines and play a role in tumor growth and progression, wound repair, and intestinal mucosal damage. However, the functional and mechanistic roles of syndecans in osteoclast differentiation and bone metabolism are yet unclear. Here, we demonstrated that post-translationally glycosylated ectodomains of syndecan-1 to 4 obtained from mammalian cells efficiently suppressed osteoclast differentiation compared to those obtained from Escherichia coli with no systems for glycosylation. A concomitant decrease in the expression of osteoclast markers such as nuclear factor of activated T cells 1 (NFATc1), c-Fos, and ATP6V0D2 was observed. In addition, heparan sulfate and selectively N-desulfated heparin derivatives with 2-O- and 6-O-sulfate groups and no anticoagulant activity in blood inhibited osteoclast differentiation. The inhibitory effects of syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives on osteoclast differentiation were attributed to their direct binding to the macrophage-colony stimulating factor (M-CSF), resulting in the blocking of M-CSF-mediated downstream signals such as extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), p38, and Akt. Furthermore, mice injected with syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives into periosteal regions of calvaria showed reduction in the formation of tartrate-resistant acid phosphatase (TRAP)-positive mature osteoclasts on the calvarial bone surface, thereby exhibiting decreased bone resorption. Together, these results revealed a novel role of heparan sulfate chains of syndecan ectodomains in the regulation of osteoclast differentiation.
Highlights
Bone formation and remodeling are regulated by the complex interplay between osteoblasts and osteoclasts in the bone marrow environment
Despite the similarity of predicted molecular weights of syndecans expressed in two different cell expression systems, the molecular weights of syndecan ectodomains from Human embryonic kidney 293E (HEK293E) cells were much higher than those of ectodomains from E. coli, suggesting that syndecan ectodomains expressed in mammalian cells may carry heparan sulfate and chondroitin sulfate side chains
We examined the effect of syndecan ectodomains on the differentiation of bone marrow-derived osteoclast precursors into osteoclasts in the presence of macrophage-colony stimulating factor (M-CSF) and RANKL
Summary
Bone formation and remodeling are regulated by the complex interplay between osteoblasts and osteoclasts in the bone marrow environment. The excessive bone resorption by osteoclasts relative to bone formation by osteoblasts leads to pathologic bone loss such as in osteoporosis, periodontal disease, cancer-associated bone. Official journal of the Cell Death Differentiation Association. Kim et al Cell Death and Disease (2018)9:1119 mononuclear osteoclast precursor fusion, followed by multinucleated osteoclast maturation[3,5]. Proteoglycans comprise a protein core that may covalently attach to at least one glycosaminoglycan (GAG) chain at specific sites[6]. Distinct structures of heparan sulfate chains in the same core protein are produced in different cell types and at different tissue sites[10]. Heparan sulfate chains have been found to bind to a wide range of cellular components such as fibroblast growth factors (FGFs) and their receptors, transforming growth factors, interleukins, bone morphogenetic proteins, lipases and apolipoproteins, and extracellular matrix proteins[9,11]
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