Department of Immunology and Cell Biology, Graduate School of Medicine & Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Department of Immunology and Cell Biology, Graduate School of Medicine & Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan; Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Bone. 2021 Nov;152:116095. doi: 10.1016/j.bone.2021.116095. Epub 2021 Jul 1.
Anti-resorptive drugs are widely used for the treatment of osteoporosis, but excessive inhibition of osteoclastogenesis can suppress bone turnover and cause the deterioration of bone quality. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is a transmembrane protein expressed on osteoclast precursor cells and mature osteoclasts. Siglec-15 regulates proteins containing immunoreceptor tyrosine-based activation motif (ITAM) domains, which then induce nuclear factor of activated T-cells 1 (NFATc1), a master transcription factor of osteoclast differentiation. Anti-Siglec-15 antibody modulates ITAM signaling in osteoclast precursors and inhibits the maturation of osteoclasts in vitro. However, in situ pharmacological effects, particularly during postmenopausal osteoporosis, remain unclear. Here, we demonstrated that anti-Siglec-15 antibody treatment protected against ovariectomy-induced bone loss by specifically inhibiting the generation of multinucleated osteoclasts in vivo. Moreover, treatment with anti-Siglec-15 antibody maintained bone formation to a greater extent than with risedronate, the first-line treatment for osteoporosis. Intravital imaging revealed that anti-Siglec-15 antibody treatment did not cause a reduction in osteoclast motility, whereas osteoclast motility declined following risedronate treatment. We evaluated osteoclast activity using a pH-sensing probe and found that the bone resorptive ability of osteoclasts was lower following anti-Siglec-15 antibody treatment compared to after risedronate treatment. Our findings suggest that anti-Siglec-15 treatment may have potential as an anti-resorptive therapy for osteoporosis, which substantially inhibits the activity of osteoclasts while maintaining physiological bone coupling.
抗吸收药物被广泛用于治疗骨质疏松症，但过度抑制破骨细胞生成会抑制骨转换并导致骨质量恶化。唾液酸结合免疫球蛋白样凝集素 15（Siglec-15）是一种表达在破骨细胞前体细胞和成骨细胞上的跨膜蛋白。Siglec-15 调节含有免疫受体酪氨酸激活基序（ITAM）结构域的蛋白质，然后诱导激活 T 细胞核因子 1（NFATc1），这是破骨细胞分化的主要转录因子。抗 Siglec-15 抗体调节破骨细胞前体中的 ITAM 信号，并在体外抑制破骨细胞的成熟。然而，其在体内的药理作用，特别是在绝经后骨质疏松症中的作用仍不清楚。在这里，我们证明抗 Siglec-15 抗体治疗通过特异性抑制体内多核破骨细胞的生成来预防卵巢切除术后的骨丢失。此外，抗 Siglec-15 抗体治疗比一线骨质疏松症治疗药物利塞膦酸钠更能维持更大程度的骨形成。活体成像显示，抗 Siglec-15 抗体治疗不会导致破骨细胞迁移减少，而利塞膦酸钠治疗后破骨细胞迁移减少。我们使用 pH 感应探针评估破骨细胞活性，发现与利塞膦酸钠治疗相比，抗 Siglec-15 抗体治疗后破骨细胞的骨吸收能力降低。我们的研究结果表明，抗 Siglec-15 治疗可能具有作为骨质疏松症抗吸收治疗的潜力，它在维持生理骨耦联的同时，能显著抑制破骨细胞的活性。
