Suppressive effect of syndecan ectodomains and N-desulfated heparins on osteoclastogenesis via direct binding to macrophage-colony stimulating factor

• Published in: Cell death & disease Vol. 9; no. 11; pp. 1119 - 13
• Main Authors: Kim, Jin-Man, Lee, Kyunghee, Kim, Mi Yeong, Shin, Hong-In, Jeong, Daewon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.11.2018; Springer Nature B.V
• Subjects: 631/443/63; 64/60; 692/163/2743/316/801; 96/1; 96/95; Acid phosphatase (tartrate-resistant); AKT protein; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone resorption; Bone turnover; c-Fos protein; c-Jun protein; Calvaria; Cell Biology; Cell Culture; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cell surface; Colonies; Colony-stimulating factor; Cytokines; Escherichia coli - genetics; Escherichia coli - metabolism; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Femur - cytology; Femur - metabolism; Glycosylation; Growth factors; Heparan sulfate; Heparan sulfate proteoglycans; Heparin; Heparin - analogs & derivatives; Heparin - chemistry; Heparin - pharmacology; Humans; Immunology; Intestine; JNK protein; Life Sciences; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - metabolism; Macrophages; Male; Mice; Mice, Inbred C57BL; Mucosa; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Osteoclastogenesis; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis - drug effects; Osteogenesis - genetics; Protein Binding; Protein Domains; Protein Processing, Post-Translational; Proteoglycans; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Syndecan-1 - genetics; Syndecan-1 - metabolism; Syndecan-1 - pharmacology; Syndecan-4 - genetics; Syndecan-4 - metabolism; Syndecan-4 - pharmacology; Transcription factors; Vacuolar Proton-Translocating ATPases - genetics; Vacuolar Proton-Translocating ATPases - metabolism; Wound healing
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1167-8

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.