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. 2023 Jul 24;11:40. doi: 10.1038/s41413-023-00262-z

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — Mechanisms by which SMAs inhibit osteoclast (OC) formation. SMAs inhibit OC formation by regulating the NF-κB, MAPKs, PK13/ATK, ORV, and other signaling pathways. OCs are large multinucleated bone-resorbing cells derived from monocytes. The preosteoclasts (pre-OCs) generated by monocytes migrate to the bone surface and fuse into multinucleated OCs through the activation of RANKL and then develop into mature OCs. RANKL is generated by OBs, osteoprogenitor cells, osteocytes, and stromal cells. M-CSF binds to the transmembrane receptor CSF-1R expressed by pre-OCs to promote the proliferation and survival of the pre-OCs. The NF-κB pathway is mediated by the upstream RANKL-RANK complex, which leads to the differentiation of pre-OCs into OCs via the activation of downstream signaling molecules such as NF-κB, c-Fos, and NFATc1. OC ruffled-border H+-ATPases (ORVs) emerge at the OC ruffled border and display novel functions in OCs to solubilize bone minerals by acidifying an extracellular resorption compartment