title: Siglec-15 is a potential therapeutic target for postmenopausal osteoporosis.
abstract: Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with an immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein, DNAX-activating protein 12kDa (DAP12). Although Siglec-15 has an important role in physiologic bone remodeling by modulating RANKL signaling, it is unclear whether it is involved in pathologic bone loss in which multiple osteoclastogenic factors participate in excessive osteoclastogenesis. Here we demonstrated that Siglec-15 is involved in estrogen deficiency-induced bone loss. WT and Siglec-15(-/-) mice were ovariectomized (Ovx) or sham-operated at 14wk of age and their skeletal phenotype was evaluated at 18 and 22wk of age. Siglec-15(-/-) mice showed resistance to estrogen deficiency-induced bone loss compared to WT mice. Although the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts increased after ovariectomy in both WT and Siglec-15(-/-) mice, the increase was lower in Siglec-15(-/-) mice than in WT mice. Importantly, osteoclasts in Siglec-15(-/-) mice were small and failed to spread on the bone surface, indicating impaired osteoclast differentiation. Because upregulated production of TNF-α as well as RANKL is mainly responsible for estrogen deficiency-induced development of osteoclasts, we examined whether Siglec-15 deficiency affects TNF-α-induced osteoclastogenesis in vitro. The TNF-α mediated induction of TRAP-positive multinucleated cells was impaired in Siglec-15(-/-) cells, suggesting that Siglec-15 is involved in TNF-α induced osteoclastogenesis. We also confirmed that signaling through osteoclast-associated receptor/Fc receptor common γ chain, which is an alternative ITAM adaptor to DAP12, rescues multinucleation but not cytoskeletal organization of TNF-α and RANKL-induced Siglec-15(-/-) osteoclasts, indicating that the Siglec-15/DAP12 pathway is especially important for cytoskeletal organization of osteoclasts in both RANKL and TNF-α induced osteoclastogenesis. The present findings indicate that Siglec-15 is involved in estrogen deficiency-induced differentiation of osteoclasts and is thus a potential therapeutic target for postmenopausal osteoporosis.
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kameda
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan. Electronic address: takamasa@med.hokudai.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahata
authors.affiliation: Hokkaido University, Laboratory of Molecular Cell Dynamics, Faculty of Advanced Life Science, Sapporo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Mikuni
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hamano
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
authors.affiliation: Hokkaido University, Department of Biochemistry, School of Medicine, Sapporo, Japan.
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Hokkaido University, Laboratory of Molecular Cell Dynamics, Faculty of Advanced Life Science, Sapporo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kinjo
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Iwasaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004967:Estrogens / Q000172:deficiency; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000172:deficiency / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D015663:Osteoporosis, Postmenopausal / Q000378:metabolism* / Q000628:therapy*; D010052:Ovariectomy; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004967:Estrogens; D007136:Immunoglobulins; D008024:Ligands; D008565:Membrane Proteins; D017452:Receptors, IgG; C582874:Siglec-15 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse
keywords: DAP12; Menopause; Osteoclast; Osteoporosis; Sialic acid; Siglec-15