The Circadian Gene Clock Regulates Bone Formation Via PDIA3

Abstract

The expression patterns of clock-controlled genes (ccgs) are regulated by circadian rhythm, which is a major regulatory and physiological mechanism tied to the solar day. Disruptions in circadian rhythm contribute to the development of cardiovascular diseases, cancer, metabolic syndromes, and aging. It has been reported that bone remodeling is also regulated by circadian rhythm. However, the molecular mechanism by which the circadian gene Clock regulates bone remodeling has yet to be elucidated. Here, we show that Clock mutant mice exhibit a significant reduction in bone density as well as increased apoptosis. Protein disulfide isomerase family A member 3 (PDIA3) is a 1,25-dihydroxy-vitamin D3 [1α,25(OH)2D3] receptor that can regulate bone formation and apoptosis. Using luciferase and ChIP assays, we confirmed that Pdia3 is a ccg. Clock activates Pdia3 transcription by binding the E-box promoter, and transcription is decreased in Clock mutant mice. Forced expression of Pdia3 or of Clock completely rescues the osteogenic disorders found in the mutant background and inhibits apoptosis in vivo and in vitro. Furthermore, ablation of PDIA3 via RNA interference completely blocks the compensatory effect of forced expression of Clock in osteoblasts. Our results demonstrate that the core circadian gene Clock regulates bone formation via transcriptional control of 1,2,5(OH)2D3 receptor PDIA3. © 2016 American Society for Bone and Mineral Research.

Circadian disruption by shifting the light‐dark cycle negatively affects bone health in mice

“…The importance of rhythm in clock gene expression for bone has been established previously by the presence of a bone phenotype in clock gene knockout mice. Mice lacking Clock or Bmal1 have a reduced bone mass, 21,24 while Per1/2 and Cry1/2 double knockout mice have an increased bone mass, 20 indicating involvement of clock genes in bone turnover. This is supported by our data demonstrating a rhythm in the expression of various bone-related genes.…”

“…14 Osteoblasts can communicate with osteoclasts by excreting receptor activator of nuclear factor κ-B ligand (RANKL), which binds to its receptor RANK on osteoclasts. 19 Furthermore, genetic disruption of clock genes affects the bone phenotype in mice, [20][21][22][23][24] suggesting a causal link between circadian physiology and bone health. Another protein secreted by osteoblasts is osteoprotegerin (OPG), which binds to RANKL and prevents it from interacting with RANK, thus preventing the bone from excessive resorption.…”

“…17 Recently, it has been shown that circulating bone turnover markers exhibit a circadian rhythm in humans 18 and are negatively affected by a combination of circadian disruption and sleep restriction. 19 Furthermore, genetic disruption of clock genes affects the bone phenotype in mice, [20][21][22][23][24] suggesting a causal link between circadian physiology and bone health. However, it remains to be elucidated whether mistimed light exposure during shift work is causally related to skeletal disorders.…”

Enabling out-of-clinic human immunity studies via single-cell profiling of capillary blood

“…Among the 20 top diurnally classified genes, we found that 50% of those genes were previously correlated with circadian behavior (Table S1), such as DDIT4 9 (Fig. 2b), SMAP2 26 , and PDIA3 36 . However, only 101/366 (27.6%) of these genes are detected as diurnal at the whole population level (FDR < 0.05, multiple comparison corrected), suggesting there may be many more diurnally-varying genes than previously discovered.…”

Identification of potential biomarkers and inhibitors in SARS-CoV-2 infected macaques

“…In the U.S., 89% of adults who have diabetes are also overweight or have obesity 18 . Obesity disrupts breathing that leads to sleep apnea and disordered sleep/wake cycle, which further causes the circadian related diseases and promotes virus infection [19][20][21][22][23][24][25] . Obesity also affects the mitochondrial structure and function 26 , which further leads to physiological dysfunction and the related diseases 27,28 .…”