Biology subjects

Vu, E. K.

Publications and source records attributed to Vu, E. K..

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↗

bioRxiv2024

CD11B+CD36+ cells are bone anabolic macrophages that limit age-associated bone loss

Disruptions in the bone remodeling cycle that occur with increasing age lead to degeneration of the skeleton and increased risk of fragility fractures. Our understanding of how bone remodeling within cortical bone is controlled and altered with age in males and females is limited. Here, we generated bone marrow chimeric mice to understand the impacts of age and sex on bone remodeling. We demonstrate that transplantation of aged male or female bone marrow into young, lethally irradiated male hosts unexpectedly enhances cortical bone mass without impacting cancellous bone. Our single cell RNA-sequencing data show that mice reconstituted with aged bone marrow exhibited subsets of cells marked by CD11B/CD36 expression that demonstrate enhanced production of anabolic cytokines as compared to young counterparts, and that these myeloid subsets exist under conditions of normal physiology in aged mice. Importantly, CD11B+CD36+ cells do not differentiate into osteoclasts in vitro, and CD36 does not mark TRAP+ cells in vivo. Instead, CD36+ cells localize to resorption sites, including within cortical bone defects, suggesting their involvement in cortical bone remodeling and healing. CD11B+CD36+ cells also express elevated levels of bone anabolic WNT ligands, especially Wnt6. In functional assays, we demonstrate that soluble factors produced by CD11B+CD36+ cells enhance osteoblast progenitor commitment, mineralization, and activation of WNT signaling in vitro. Moreover, CD11B/CD36 exquisitely mark a subset of anabolic myeloid cells within human bone marrow. In conclusion, our studies identified a novel population of aged macrophages that limit cortical bone loss.

cell biology↗