Loss of the circadian regulator Per1 promotes osteoclastogenesis and bone resorption.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE292534 | GEO | 2026/02/12
REPOSITORIES: GEO
Dataset's files
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| GSE292534_gene_fpkm_Per2x12.xlsx | Xlsx |
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Project description:Bone remodeling is regulated by circadian rhythms but molecular details remain largely unknown. Here, we show that osteoclastogenesis was promoted in mononuclear phagocyte-specific knockout (conditional KO or cKO) mice of Per1, one of the core regulators for circadian rhythms. The bone mass was decreased in the cortex and trabecular bones of the tibia, accompanied by increased osteoclasts compared with control (Cont) mice. cKO also increased the number and the size of osteoclasts differentiated from bone marrow macrophages in vitro. At the molecular level, cKO downregulated inflammasome genes and downstream IL1b and IL18, which were directly regulated by the PER1 protein at the promoters. Downregulation of these genes were known to promote osteoclastogenesis. This study provides a novel link between a circadian regulator and bone remodeling, which could be relevant to osteoporosis in shift workers.
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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.
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