The actin-bundling protein L-plastin (LPL) mediates the resorption activity of osteoclasts, but its therapeutic potential in pathological bone loss remains unexplored. Here, we report that LPL knockout mice show increased bone mass and cortical thickness with more mononuclear tartrate-resistant acid phosphatase–positive cells, osteoblasts, CD31^hiEmcn^hi endothelial vessels, and fewer multinuclear osteoclasts in the bone marrow and periosteum. LPL deletion impeded preosteoclasts fusion by inhibiting filopodia formation and increased the number of preosteoclasts, which release platelet-derived growth factor-BB to promote CD31^hiEmcn^hi vessel growth and bone formation. LPL expression is regulated by the phosphatidylinositol 3-kinase/AKT/specific protein 1 axis in response to receptor activator of nuclear factor–κB ligand. Furthermore, we identified an LPL inhibitor, oroxylin A, that could maintain bone mass in ovariectomy-induced osteoporosis and accelerate bone fracture healing in mice. In conclusion, we showed that LPL regulates osteoclasts fusion, and targeting LPL serves as a novel anabolic therapy for pathological bone loss.

肌动蛋白捆绑蛋白 L-plastin (LPL) 介导破骨细胞的再吸收活性，但其在病理性骨丢失中的治疗潜力仍未得到探索。在这里，我们报告 LPL 敲除小鼠的骨量和皮质厚度增加，具有更多的单核抗酒石酸酸性磷酸酶阳性细胞、成骨细胞、CD31 ^hi Emcn ^hi内皮血管，以及骨髓和骨膜中更少的多核破骨细胞。LPL 缺失通过抑制丝状伪足形成阻碍前破骨细胞融合，增加破骨前细胞数量，释放血小板衍生生长因子-BB 促进 CD31 ^hi Emcn ^hi血管生长和骨骼形成。LPL 表达受磷脂酰肌醇 3-激酶/AKT/特异性蛋白 1 轴的调节，以响应核因子-κB 配体的受体激活剂。此外，我们发现了一种 LPL 抑制剂 oroxylin A，它可以在卵巢切除术引起的骨质疏松症中维持骨量并加速小鼠骨折的愈合。总之，我们发现 LPL 调节破骨细胞融合，靶向 LPL 可作为病理性骨丢失的新型合成代谢疗法。