Osteoporosis (OP) is a common age-related disease characterized by a deterioration of bone mass and structure that predisposes patients to fragility fractures. Pharmaceutical therapies that promote anabolic bone formation in OP patients and OP-induced fracture are needed. We investigated whether a neutralizing antibody against Siglec-15 can simultaneously inhibit bone resorption and stimulate bone formation. We found that the multinucleation of osteoclasts was inhibited in SIGLEC-15 conditional knockout mice and mice undergoing Siglec-15 neutralizing antibody treatment. The secretion of platelet-derived growth factor-BB (PDGF-BB), the number of tartrate-resistant acid phosphatase-positive (TRAP⁺) mononuclear cells, and bone formation were significantly increased in the SIGLEC-15 conditional knockout mice and antibody-treated mice. The anabolic effect of the Siglec-15 neutralizing antibody on bone formation was blunted in mice with Pdgfb deleted in TRAP⁺ cells. These findings showed that the anabolic effect of the Siglec-15 neutralizing antibody was mediated by elevating PDGF-BB production of TRAP⁺ mononuclear cells. To test the therapeutic potential of the Siglec-15 neutralizing antibody, we injected the antibody in an ovariectomy-induced osteoporotic mouse model, which mimics postmenopausal osteoporosis in women, and in two fracture healing models because fracture is the most serious health consequence of osteoporosis. The Siglec-15 neutralizing antibody effectively reduced bone resorption and stimulated bone formation in estrogen deficiency-induced osteoporosis. Of note, the Siglec-15 neutralizing antibody promoted intramembranous and endochondral ossification at the damaged area of cortical bone in fracture healing mouse models. Thus, the Siglec-15 neutralizing antibody shows significant translational potential as a novel therapy for OP and bone fracture.

骨质疏松症 (OP) 是一种常见的与年龄相关的疾病，其特征是骨量和结构恶化，使患者易患脆性骨折。需要促进 OP 患者和 OP 诱导的骨折的合成代谢骨形成的药物疗法。我们研究了针对 Siglec-15 的中和抗体是否可以同时抑制骨吸收和刺激骨形成。我们发现，在SIGLEC-15条件性敲除小鼠和接受 Siglec-15 中和抗体治疗的小鼠中，破骨细胞的多核化受到抑制。血小板源性生长因子-BB（PDGF-BB）的分泌、抗酒石酸酸性磷酸酶阳性（TRAP ⁺）单核细胞的数量和骨形成均显着增加。SIGLEC-15条件敲除小鼠和抗体处理小鼠。Siglec-15 中和抗体对骨形成的合成代谢作用在 TRAP ⁺细胞中缺失Pdgfb 的小鼠中减弱。这些发现表明 Siglec-15 中和抗体的合成代谢作用是通过提高 TRAP ⁺ PDGF-BB 的产生来介导的。单核细胞。为了测试 Siglec-15 中和抗体的治疗潜力，我们将抗体注射到卵巢切除诱导的骨质疏松小鼠模型中，该模型模拟了女性绝经后骨质疏松症，以及两种骨折愈合模型，因为骨折是骨质疏松症最严重的健康后果。Siglec-15 中和抗体有效地减少了骨吸收并刺激了雌激素缺乏引起的骨质疏松症的骨形成。值得注意的是，Siglec-15 中和抗体在骨折愈合小鼠模型中促进了皮质骨受损区域的膜内和软骨内骨化。因此，Siglec-15 中和抗体显示出作为 OP 和骨折新疗法的显着转化潜力。