Biology subjects

Katoku-Kikyo, N.

Publications and source records attributed to Katoku-Kikyo, N..

3 recordsLinked to original sources

bioRxiv2026

Circadian regulators PER1 and PER2 regulate osteoclastogenesis by balancing competing activities of innate immunity genes

Bone remodeling is influenced by circadian rhythms as demonstrated by global gene expression patterns and the phenotypes of knockout mice of circadian regulators. However, the direct connections between circadian regulators and specific bone genes remain unclear. We previously found that a conditional knockout of Per1, a central circadian regulator, in osteoclasts increased osteoclastogenesis and decreased bone mass, whereas Per2 knockout did not cause these phenotypes. Here, we extended the research to Per1;Per2 conditional double knockout mice and observed different phenotypes and underlying mechanisms from individual knockouts. In contrast to Per1 knockout, the double knockout decreased osteoclastogenesis and increased bone mass. This was accompanied by downregulation of genes involved in innate immunity, including several known promoters and inhibitors of osteoclastogenesis. Chromatin immunoprecipitation and reporter assay suggested direct regulation of some of them by PER proteins. These results indicate that PER1 and PER2 are critical regulators of osteoclastogenesis through balancing multiple competing activities of osteoclastogenesis, rather than acting as simple promoters or inhibitors of osteoclastogenesis. Regulation of innate immunity genes by circadian regulators is widely observed across other monocyte/macrophage lineages. Our results extend this common mechanism to osteoclasts with therapeutic potential to treat inflammatory bone diseases. Lay summaryAlthough circadian rhythms regulate bone remodeling, direct links between circadian regulators and bone genes remain unclear. We previously demonstrated that depletion of Per1, a main circadian regulator, downregulates immunological genes, increases the number of osteoclasts, the main bone resorbing cells, and decreases bone mass in mice. Here, we showed the opposite effects with double depletion of Per1 and Per2 and identified a new set of downregulated immunological genes that promote or inhibit osteoclastogenesis. This study connects circadian rhythms to bone resorption through immunological genes with opposing activities in osteoclastogenesis, supporting therapeutic interventions targeting circadian regulators to treat inflammatory bone diseases.

cell biology↗

bioRxiv2025

The circadian regulator PER1 inhibits osteoclastogenesis by activating inflammatory genes

Disruption of circadian rhythms predisposes shift workers to many chronic conditions, including osteoporosis. However, the effects of disrupted circadian rhythms on bone remodeling remain largely unknown. Here, we show that one of the core circadian regulators PER1 inhibits osteoclastogenesis by upregulating genes involved in inflammation. The conditional knockout of Per1 in osteoclasts and related cells resulted in decreased bone mass in the femurs of mice, along with increased osteoclasts and decreased osteoblasts. Osteoclastogenesis was also promoted by Per1 depletion in vitro with 16 downregulated inflammatory genes. Seven of these genes were known to promote or inhibit osteoclastogenesis depending on the stage of osteoclastogenesis and the presence or absence of infection. Knockdown of Nlrp3, Tlr8, or Tlr9 in the group of genes promoted osteoclastogenesis, mirroring the effects of Per1 knockout and offering a mechanistic explanation for the Per1-mediated inhibition of osteoclastogenesis. These results were not observed following the knockout of a paralog Per2. Per1 knockout mice maintain general circadian rhythms, unlike arrhythmic Per1;Per2 double knockout mice. This gives credence to Per1 as a selective target for therapeutic interventions without disrupting the circadian rhythms. This study uncovered a molecular link between a circadian regulator and osteoclastogenesis in the broader context of inflammatory reactions. Our findings may be mechanistically relevant to inflammatory bone diseases influenced by circadian rhythms, such as rheumatoid arthritis and osteoarthritis, as well as other bone diseases predisposed by chronic circadian disruption. Lay summaryDisruption of circadian rhythms is a risk factor for many chronic diseases, including osteoporosis, among shift workers; however, underlying mechanisms remain largely unknown. In this study, the depletion of Per1, a core circadian regulator, resulted in an increase in bone-resorbing osteoclasts and a decrease in bone mass in mice. These changes were accompanied by a decrease in the expression of inflammatory genes that promoted the formation of osteoclasts upon depletion. This study revealed a link between circadian rhythms and bone loss, with inflammatory genes serving as mediators, which could provide a basis for future therapeutic interventions.

developmental biology↗

bioRxiv2020

Circadian timing-dependent myoblast differentiation and muscle regeneration

Circadian rhythms regulate cell proliferation and differentiation but circadian control of tissue regeneration remains elusive at the molecular level. Here, we show that proper myoblast differentiation and muscle regeneration are regulated by the circadian master regulators Per1 and Per2. Depletion of Per1 or Per2 suppressed myoblast differentiation in vitro and muscle regeneration in vivo, demonstrating their non-redundant functions. Both Per1 and Per2 were required for the activation of Igf2, an autocrine promoter of myoblast differentiation, accompanied by Per-dependent recruitment of RNA polymerase II, dynamic histone modifications at the Igf2 promoter and enhancer, and the promoter-enhancer interaction. This circadian epigenetic priming created a preferred time window for initiating myoblast differentiation. Consistently, muscle regeneration was faster if initiated at night when Per1, Per2, and Igf2 were highly expressed compared with morning. This study reveals the circadian timing as a significant factor for effective muscle cell differentiation and regeneration. eTOC SummaryKatoku-Kikyo et al. show that the circadian master regulators Per1 and Per2 control the efficiency of myoblast differentiation via Igf2 activation. This pathway creates a preferred circadian time window for myoblast differentiation in vitro and muscle regeneration in vivo.

developmental biology↗