Siglec-15 is a potential therapeutic target for postmenopausal osteoporosis

• We investigated whether blockade of Siglec-15 is effective for preventing estrogen deficiency-induced bone loss in a mouse ovariectomy model.
• Siglec-15−/− mice showed resistance to estrogen deficiency-induced bone loss.
• Osteoclast development was impaired in ovariectomized Siglec-15−/− mice.
• The TNF-α mediated induction of TRAP-positive multinucleated cells was impaired in Siglec-15−/− cells.

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 12 kDa (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 14 wk of age and their skeletal phenotype was evaluated at 18 and 22 wk 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.