The circadian regulator PER1 inhibits osteoclastogenesis by activating inflammatory genes

No SJR dataSep 26, 2025bioRxiv : the preprint server for biology

The body’s daily clock protein PER1 slows bone breakdown by turning on inflammation-related genes

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Abstract

Disruption of circadian rhythms may lead to decreased bone mass and increased osteoclasts in mice.

The core circadian regulator PER1 inhibits the formation of osteoclasts by increasing the expression of inflammation-related genes.
Mice with a conditional knockout of PER1 in osteoclasts showed lower bone mass in their femurs and higher osteoclast counts compared to controls.
In vitro studies indicated that depletion of 17 inflammatory genes promotes osteoclast formation.
Some genes involved in the inflammasome pathway, when knocked down, also increased osteoclastogenesis, providing insight into the mechanisms involved.
Knockout mice that maintained general circadian rhythms demonstrated different outcomes compared to those with disrupted rhythms, suggesting potential therapeutic targeting.

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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 ofin 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 bydepletion in vitro with 17 downregulated inflammatory genes. Eight of these genes were known to promote or inhibit osteoclastogenesis depending on the stage of osteoclastogenesis and the presence or absence of infection. The knockdown of three of these genes, which were involved in the inflammasome pathway, promoted osteoclastogenesis, mirroring the effects ofknockout and offering a mechanistic explanation for the-mediated inhibition of osteoclastogenesis. These results were not observed following the depletion of a paralog.knockout mice maintain general circadian rhythms, unlike arrhythmic/double knockout mice. This gives credence toas a selective target for therapeutic interventions without disrupting the circadian rhythms. This study uncovered a link between a circadian regulator and osteoclastogenesis in the broader context of osteoimmunology. 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. Per1Per1Per1Per1Per2Per1Per1Per2Per1

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