Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation
Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation
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DOI：
10.1016/j.bone.2021.116095
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发表时间：
2021-07-07
期刊：
影响因子：
4.1
通讯作者：
Ishii, Masaru
中科院分区：
文献类型：
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作者：
Tsukazaki, Hiroyuki;Kikuta, Junichi;Ishii, Masaru
抗骨吸收药物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，导致骨质量恶化。唾液酸结合免疫球蛋白样凝集素 15 (Siglec-15) 是一种在破骨细胞前体细胞和成熟破骨细胞上表达的跨膜蛋白。 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 抗体可调节破骨细胞前体中的 ITAM 信号传导并抑制破骨细胞的体外成熟。然而，原位药理作用，特别是绝经后骨质疏松症期间的药理作用仍不清楚。在这里，我们证明抗 Siglec-15 抗体治疗可以通过特异性抑制体内多核破骨细胞的生成来防止卵巢切除术引起的骨质流失。此外，与骨质疏松症一线治疗药物利塞膦酸盐相比，抗 Siglec-15 抗体治疗更能维持骨形成。活体成像显示，抗Siglec-15抗体治疗不会导致破骨细胞活力降低，而利塞膦酸盐治疗后破骨细胞活力下降。我们使用 pH 传感探针评估破骨细胞活性，发现抗 Siglec-15 抗体治疗后破骨细胞的骨吸收能力低于利塞膦酸盐治疗后。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，它可以显着抑制破骨细胞的活性，同时维持生理性骨耦合。
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 antiSiglec-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 antiresorptive therapy for osteoporosis, which substantially inhibits the activity of osteoclasts while maintaining physiological bone coupling.