The Interaction between Bmal1 and Per2 in Mouse BMSC Osteogenic Differentiation

Abstract

The circadian clock is a system that controls endogenous time of organisms, and it regulates the physiology and behavior of bodies. The transcription factors Brain and Muscle ARNT-like Protein 1 (BMAL1) and Period2 (Per2) are components of the circadian clock, and they play vital roles in circadian clock function. Both Bmal1−/− mice and Per2−/− mice display obvious bone volume changes. In this study, we inhibited the expression of Bmal1 in bone marrow-derived mesenchymal stem cells (BMSCs) using a lentiviral vector harboring RNAi sequences, which increased the osteogenic differentiation capability of BMSCs. We also suppressed Per2 gene expression using an adenovirus vector harboring RNAi sequences, and similarly, the osteogenic differentiation ability of BMSCs was enhanced. Furthermore, when both Bmal1 and Per2 gene expression was suppressed in BMSCs by lentiviral and adenoviral interference, the osteogenic differentiation capability was stronger than that in BMSCs following single-gene inhibition. Our data support that both Bmal1 and Per2 play negative roles in BMSC osteogenic differentiation and that Bmal1 and Per2 have a synergistic effect on the osteogenic differentiation of BMSCs.

Circadian transcription factor Dbp promotes rat calvarial osteoprogenitors osteogenic differentiation through Kiss1/GnRH/E2 signaling pathway loop

“…Recently, various studies have indicated that these circadian clock genes serve a crucial role in modulating the behavior of mesenchymal stem cells involved in bone homeostasis and rehabilitation. [34][35][36]38,[47][48][49] However, the conclusions of these findings are not always consistent. 36,50 One study reported that Bmal1 knockout mice have impaired BMSCs differentiation under osteogenic conditions, and a reduced number of both active osteoblasts and osteocytes 36 ; while another study observed an increase in osteoblast activity in Bmal1 knockout mice.…”

“…While previous studies have identified a correlation between the circadian clock and bone homeostasis, [34][35][36][37][38] an understanding of the underlying mechanism whereby the circadian clock to modulate bone and cartilage homeostasis and metabolism is pivotal to ensure a more accurate treatment time for chronic diseases, such as osteoporosis, osteoarthritis, or other age-related bone degeneration.…”

“…50 Furthermore, in another BMSC study, Bmal1 and Per2 expression was inhibited using RNAi and showed that Bmal1 and Per2 have a negative synergistic effect on BMSC osteogenic differentiation. 38 Maronde et al 35 found that the single knockout of Per2 or Cry2 affected bone formation in 12-week-old mice, with the Per2 knockout associated with increased osteoblast activity and an increased bone formation rate, while the Cry2 knockout was associated with a decreased osteoclast activity. However, when a double knockout was performed with these genes, the osteoclast activity remained deficient and the bone formation rate was reduced.…”

“…Recently, various studies have indicated that these circadian clock genes serve a crucial role in modulating the behavior of mesenchymal stem cells involved in bone homeostasis and rehabilitation 34‐36,38,47‐49 . However, the conclusions of these findings are not always consistent 36,50 .…”

The period circadian clock 2 gene responds to glucocorticoids and regulates osteogenic capacity

“…Recently, Zhou et al. (2018) reported that osteogenic differentiation of bone marrow stem cells (BMSCs) in vitro is enhanced when RNA interference techniques are used to inhibit the expression of Arntl/Bmal1 or Per2 , indicating that ARNTL/BMAL1 and PER2 negatively regulate the osteogenic potential of BMSCs and may have a synergistic effect on the osteogenic differentiation of BMSCs [33]. We show here that the proliferation of osteoblast derived from mPer2 m/m mice was enhanced compared with those of WT mice, suggesting that an absence of PER2 shortens the cell cycle and the biological clock.…”