The circadian regulator PER1 inhibits osteoclastogenesis by activating inflammatory genes

Abstract

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.