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

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.