Osteoclast differentiation by RANKL and OPG signaling pathways
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INVITED REVIEW
Osteoclast differentiation by RANKL and OPG signaling pathways Nobuyuki Udagawa1,2 · Masanori Koide2 · Midori Nakamura1,2 · Yuko Nakamichi2 · Teruhito Yamashita2 · Shunsuke Uehara1 · Yasuhiro Kobayashi2 · Yuriko Furuya3 · Hisataka Yasuda3 · Chie Fukuda4 · Eisuke Tsuda4 Received: 19 July 2020 / Accepted: 22 September 2020 © The Japanese Society Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2020
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. Keywords Osteoclast · Osteoblast · Bone resorption · RANKL · OPG
Introduction
* Nobuyuki Udagawa [email protected] 1
Department of Biochemistry, Matsumoto Dental University, 1780 Gobara, Hiro‑oka, Shiojiri, Nagano 399‑0781, Japan
2
Division of Hard Tissue Research, I, nstitute for Oral Science, Matsumoto Dental University, Nagano 399‑0781, Japan
3
Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., Nagahama, Japan
4
Specialty Medicine Research Laboratories 1, Daiichi Sankyo Co., Ltd., Tokyo, Japan
Bone is continuously destroyed by osteoclas
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