Circadian regulators PER1 and PER2 control osteoclastogenesis in male mice through coordinated regulation of opposing innate immunity genes

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ID: 327682
2026
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Ranked #30 of 143 articles by views in journal of bone and mineral research : the official journal of the american society for bone and mineral research

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Abstract
Abstract Bone remodeling is regulated by circadian rhythm, yet the molecular mechanisms linking circadian clock components to osteoclast function remain largely undefined. We previously showed that osteoclast-specific deletion of Per1, a core circadian regulator, increased osteoclastogenesis and reduced bone mass in male mice, whereas deletion of Per2 had little effect. Here, we investigated Per1;Per2 conditional double-knockout (dKO) mice and unexpectedly found the opposite phenotype. In contrast to Per1 deficiency, dKO suppressed osteoclastogenesis and increased bone mass specifically in male mice, revealing previously unrecognized functional interactions between PER1 and PER2 in osteoclasts. Transcriptomic analyses showed that dKO osteoclasts preferentially downregulated innate immunity genes, including both positive and negative regulators of osteoclastogenesis. Chromatin immunoprecipitation and reporter assays further identified innate immunity genes as downstream targets of PER-dependent circadian regulation. These findings indicate that PER1 and PER2 regulate osteoclastogenesis through coordinated control of a network of immune genes with opposing effects on osteoclast differentiation, rather than acting as simple promoters or inhibitors of bone resorption. More broadly, this study establishes innate immunity as a mechanistic interface between the circadian clock and osteoclast function, providing a framework for understanding how circadian disruption influences bone remodeling and inflammatory bone diseases.
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Authors Nobuko Katoku-Kikyo, Elizabeth K. Vu, Samuel Mitchell, Ismael Y. Karkache, Emily Patterson, Elizabeth W. Bradley, Nobuaki Kikyo
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Journal journal of bone and mineral research : the official journal of the american society for bone and mineral research
Year 2026
DOI
10.1093/jbmr/zjag131
URL
https://doi.org/10.1093/jbmr/zjag131
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