Osteoclastic ATP6AP2 maintains β-catenin levels to prevent hyper-osteoclastic activation and trabecular bone-loss.

Autor:	Chen L; Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun, Jilin 130022, China.; Department of Neurosciences, School of Medicine, Case Western Reserve University, 2210 Circle Dr Building, Cleveland, OH 44106, United States., Xiong L; Department of Neurosciences, School of Medicine, Case Western Reserve University, 2210 Circle Dr Building, Cleveland, OH 44106, United States.; Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Blvd, Cleveland, OH 44106, United States., Guo H; Department of Neurosciences, School of Medicine, Case Western Reserve University, 2210 Circle Dr Building, Cleveland, OH 44106, United States.; Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Blvd, Cleveland, OH 44106, United States., Feng X; Department of Pathology, School of Medicine, University of Alabama at Birmingham, 619 19th St S Ste P210, Birmingham, AL 35233, United States., Zhu X; Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun, Jilin 130022, China., Xiong WC; Department of Neurosciences, School of Medicine, Case Western Reserve University, 2210 Circle Dr Building, Cleveland, OH 44106, United States.; Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Blvd, Cleveland, OH 44106, United States.
Jazyk:	angličtina
Zdroj:	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2024 Nov 29; Vol. 39 (12), pp. 1821-1834.
DOI:	10.1093/jbmr/zjae164
Abstrakt:	Osteoclast (OC) formation and bone resorption are regulated by several factors, including V-ATPase, Wnt/β-catenin, and RANKL/RANK signaling. ATP6AP2, also known as the prorenin receptor (PRR), is an accessory subunit of V-ATPase and a regulator of Wnt/β-catenin signaling. While the V-ATPase subunit ATP6AP1 is essential for OC formation and function, the role of ATP6AP2 in OC-lineage cells is less clear. Here, we provide evidence that ATP6AP2 plays a negative role in osteoclastogenesis and function, contrasting with the positive role of ATP6AP1. Mice with conditional KO (cKO) of ATP6AP2 in OCs (Atp6ap2LysM) exhibit trabecular bone loss, likely due to the increased osteoclastogenesis and activity, since bone formation rates (BFRs) are comparable to control mice. In vitro assays using bone marrow macrophages (BMMs) show that Atp6ap2LysM cultures have more RANKL-induced TRAP+ OC-like cells and increased bone resorptive activity. Further studies reveal that while RANKL signaling and V-ATPase activity are normal, ATP6AP2 KO OCs, but not BMMs, have reduced basal levels of Wnt/β-catenin pathway proteins, such as LRP5/6 and β-catenin, compared to controls. Wnt3A treatment induces β-catenin and suppresses OC formation in both control and ATP6AP2 KO OC-lineage cells, indicating that Wnt/β-catenin signaling negatively regulates OC-formation and operates independently of ATP6AP2. Overall, these results suggest that ATP6AP2 is critical for maintaining basal levels of LRP5/6 receptors and β-catenin in OCs, thus acting as a negative regulator of osteoclastogenesis and activation. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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