Signaling pathway mechanisms of circadian clock gene Bmal1 regulating bone and cartilage metabolism: a review

Abstract

Circadian rhythm is ubiquitous in nature. Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network, and regulate a variety of physiological and pathological processes, including bone and cartilage metabolism. Deletion of the core clock gene Bmal1 leads to pathological bone alterations, while the phenotypes are not consistent. Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism, but the exact regulatory mechanisms remain unclear. This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism, the upstream regulatory factors that control Bmal1, and the current Bmal1 knockout mouse models for research. We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.

Fig. 1

Circadian rhythm influences bone/cartilage metabolism. Endochondral ossification involves the formation of cartilage template, differentiation and proliferation of chondrocytes, and gradual replacement by osteoblasts, resulting in bone formation. Intramembranous ossification entails the gradual differentiation of MSCs within soft tissues (or damaged tissues) into osteoblasts, followed by the formation of primary bone spicules and gradual deposition of mature bone tissue. Under physiological conditions, bone formation and resorption are dynamically balanced. Clock genes have been implicated in the regulation of the aforementioned bone/cartilage metabolism processes through various signaling pathways or networks

Fig. 2

Schematic diagram of Bmal1 involving in different signaling pathways. We include the key components of these pathways and mark the effect targets of Bmal1. Notably, due to the lack of conclusive results regarding the binding sites and specific regulatory mechanisms of Bmal1, we use dashed arrows to indicate the indirect effect of Bmal1, either up- or down-regulating the expression of downstream molecules, whereas solid arrows/inhibition symbols to represent relatively clear direct promotion/inhibition effects