Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation
| Autor: | Akito Morimoto, Chie Fukuda, Hiroyuki Tsukazaki, Masaru Ishii, Takashi Kaito, Kazuya Kikuchi, Tomoka Ao, Masafumi Minoshima, Eisuke Tsuda, Junichi Kikuta |
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| Rok vydání: | 2021 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Histology Physiology Endocrinology Diabetes and Metabolism Osteoporosis Motility Osteoclasts 030209 endocrinology & metabolism Bone resorption Bone and Bones Bone remodeling 03 medical and health sciences 0302 clinical medicine Multinucleate Osteoclast Osteogenesis Precursor cell medicine Humans Bone Resorption NFATC Transcription Factors Chemistry RANK Ligand SIGLEC Cell Differentiation respiratory system medicine.disease 030104 developmental biology medicine.anatomical_structure Cancer research Female |
| Zdroj: | Bone. 152 |
| ISSN: | 1873-2763 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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