Abstract Bone regeneration is initiated after a bone injury, such as a bone fracture or tooth extraction. It is a highly complex biological process involving multiple cell types, signaling molecules, and molecular pathways. The hypoxic microenvironment in the early stage of bone regeneration poses challenges to cell status and the final outcome of bone regeneration. During this phase, two key regulators—HIF-1α (the critical mediator of hypoxia response) and BMAL1 (the central component of the circadian rhythm)—orchestrate the activities of bone-regenerating cells, ensuring proper cellular function and orderly progression of bone repair. Existing studies have shown that there is a close crosstalk between HIF-1α and BMAL1, including regulation of gene expression, protein interaction, and regulation of downstream pathways. In this review, we discuss the respective regulatory roles of HIF-1α and BMAL1 in bone regeneration and further summarize their interactions within cells. Additionally, we extend the discussion to their interactions in other bone-related diseases, and summarize the existing research directions and deficiencies, providing new insights for in-depth studies of the hypoxia response and circadian rhythm systems.
Weng et al. (2026) studied this question.