WDR23 prevents bone loss by promoting autophagic degradation of TRAF6 in osteoclastogenesis.

Authors

Hye-Won Park, Jungeun Yu, Jiyeon Yu, Jinseon You, Yeon Hee Kook, Joo-Yong Lee, Taesoo Kim, Chul-Ho Lee, Hee-Chung Chung, Jong-Soon Choi, Sangkyu Lee, Jaerang Rho

Published in

Bone research. Volume 14. Issue 1. Sep 10, 2026. Epub Sep 10, 2026.

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a pivotal adaptor molecule in the receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) signaling pathways, which are essential for osteoclastogenesis. In this study, we identified WD40 repeat-containing protein 23 (WDR23), also known as DDB1-CUL4 associated factor 11 (DCAF11), as a novel binding partner of TRAF6. Our findings demonstrate that WDR23/DCAF11 acts as a negative feedback regulator of RANK/RANKL-induced osteoclastogenesis by promoting the autophagy-dependent degradation of TRAF6. Notably, RANKL induced the upregulation of WDR23 expression during osteoclastogenesis. WDR23 physically interacted with the TRAF domain of TRAF6 via the WD40 repeat domains 1 and 2 of WDR23, resulting in reduced TRAF6 protein stability by its autophagy-dependent degradation during osteoclastogenesis. By modulating TRAF6 protein levels, WDR23 attenuated RANKL signaling cascades, including nuclear factor-κB and mitogen-activated protein kinases, thereby downregulating the expression of osteoclastogenic markers, such as nuclear factor of activated T-cell c1, tartrate-resistant acid phosphatase, dendritic cell-specific transmembrane protein, V-ATPase subunit d2 and cathepsin K. Conversely, WDR23 knockdown or deficiency enhanced RANKL-induced osteoclastogenesis by preventing the autophagy-dependent degradation of TRAF6. WDR23-deficient mice exhibit an osteoporotic bone phenotype characterized by elevated osteoclast formation and reduced bone mass. Collectively, these results establish WDR23 as a key negative feedback regulator of RANKL-induced osteoclastogenesis via autophagy-mediated TRAF6 degradation and underscore its potential as a therapeutic target for bone disorders associated with aberrant osteoclast formation and function.

PMID:
42717193
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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