Osteoclasts are multinucleated cells responsible for bone resorption. Src homology 3 (SH3) domain‐containing protein‐2 (SH3P2)/osteoclast‐stimulating factor‐1 regulates osteoclast differentiation, but its exact role remains elusive. Here, we show that SH3P2 suppresses osteoclast differentiation. SH3P2 knockout (KO) mice displayed decreased femoral trabecular bone mass and enhanced localization of osteoclasts on the tibial trabecular bone surface, suggesting that SH3P2 suppresses bone resorption by osteoclasts. Osteoclast differentiation based on cellular multinuclearity induced by macrophage colony‐stimulating factor and receptor activator of nuclear factor‐κB ligand (RANKL) was enhanced in bone marrow‐derived macrophages lacking SH3P2. RANKL induced SH3P2 dephosphorylation, which increased the association of actin‐dependent motor protein myosin 1E (Myo1E) with SH3P2 and thereby prevented Myo1E localization to the plasma membrane. Consistent with this, Myo1E in the membrane fraction increased in SH3P2‐KO cells. Together with the attenuated osteoclast differentiation in Myo1E knocked down cells, SH3P2 may suppress osteoclast differentiation by preventing their cell‐to‐cell fusion depending on Myo1E membrane localization.

中文翻译：

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SH3P2 通过限制肌球蛋白 1E 的膜定位来抑制破骨细胞分化。

破骨细胞是负责骨吸收的多核细胞。含有 Src 同源 3 (SH3) 结构域的蛋白-2 (SH3P2)/破骨细胞刺激因子-1 调节破骨细胞分化，但其确切作用仍然难以捉摸。在这里，我们表明 SH3P2 抑制破骨细胞分化。SH3P2 敲除 (KO) 小鼠显示股骨小梁骨量减少和破骨细胞在胫骨小梁骨表面的​​定位增强，表明 SH3P2 抑制破骨细胞的骨吸收。在缺乏 SH3P2 的骨髓来源的巨噬细胞中，基于巨噬细胞集落刺激因子和核因子-κB 配体 (RANKL) 受体激活因子诱导的破骨细胞分化得到增强。RANKL 诱导 SH3P2 去磷酸化，这增加了肌动蛋白依赖性运动蛋白肌球蛋白 1E (Myo1E) 与 SH3P2 的关联，从而阻止 Myo1E 定位到质膜。与此一致，SH3P2-KO 细胞膜部分中的 Myo1E 增加。与 Myo1E 敲低细胞中破骨细胞分化减弱一起，SH3P2 可能通过阻止破骨细胞的细胞间融合来抑制破骨细胞分化，这取决于 Myo1E 膜定位。