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Osteoclast differentiation by RANKL and OPG signaling pathways

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Abstract

Introduction

In bone tissue, bone resorption by osteoclasts and bone formation by osteoblasts are repeated continuously. Osteoclasts are multinucleated cells that derive from monocyte-/macrophage-lineage cells and resorb bone. In contrast, osteoblasts mediate osteoclastogenesis by expressing receptor activator of nuclear factor-kappa B ligand (RANKL), which is expressed as a membrane-associated cytokine. Osteoprotegerin (OPG) is a soluble RANKL decoy receptor that is predominantly produced by osteoblasts and which prevents osteoclast formation and osteoclastic bone resorption by inhibiting the RANKL–RANKL receptor interaction.

Materials and Methods

In this review, we would like to summarize our experimental results on signal transduction that regulates the expression of RANKL and OPG.

Results

Using OPG gene-deficient mice, we have demonstrated that OPG and sclerostin produced by osteocytes play an important role in the maintenance of cortical and alveolar bone. In addition, it was shown that osteoclast-derived leukemia inhibitory factor (LIF) reduces the expression of sclerostin in osteocytes and promotes bone formation. WP9QY (W9) is a peptide that was designed to be structurally similar to one of the cysteine-rich TNF-receptortype-I domains. Addition of the W9 peptide to bone marrow culture simultaneously inhibited osteoclast differentiation and stimulated osteoblastic cell proliferation. An anti-sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) antibody inhibited multinucleated osteoclast formation induced by RANKL and macrophage colony-stimulating factor (M-CSF). Pit-forming activity of osteoclasts was also inhibited by the anti-Siglec-15 antibody. In addition, anti-Siglec-15 antibody treatment stimulated the appearance of osteoblasts in cultures of mouse bone marrow cells in the presence of RANKL and M-CSF.

Conclusions

Bone mass loss depends on the RANK–RANKL–OPG system, which is a major regulatory system of osteoclast differentiation induction, activation, and survival.

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Acknowledgements

This work was supported by JSPS KAKENHI (Grant nos 19K10395, 17K19776, 16H05508, 16K11818, 15K11377, and 15K15688).

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Correspondence to Nobuyuki Udagawa.

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Eisuke Tsuda and Chie Fukuda are employees of Daiichi Sankyo Co., Ltd. The other authors (Nobuyuki Udagawa, Masanori Koide, Midori Nakamura, Yuko Nakamichi, Teruhito Yamashita, Shunsuke Uehara, and Yasuhiro Koide) have financial interest and/or other relationship with Daiichi Sankyo Co., Ltd. Yuriko Furuya and Hisataka Yasuda are employees of Oriental Yeast Co., Ltd.

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All experiments performed in the Matsumoto Dental University were conducted in strict accordance with the Guidelines for Studies with Laboratory Animals of the Matsumoto Dental University Experimental Animal Committee.

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Udagawa, N., Koide, M., Nakamura, M. et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab 39, 19–26 (2021). https://doi.org/10.1007/s00774-020-01162-6

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