Bone Resorption Is Regulated by Circadian Clock in Osteoblasts.

Area of Science:

• Endocrinology
• Chronobiology
• Skeletal Biology

Background:

• The Clock system, comprising core components like Bmal1 and Per1, regulates circadian rhythms.
• Previous research indicated the Clock system's role in chondrocyte-mediated endochondral ossification.
• The specific role of the Clock system within osteoblasts in regulating bone mass and resorption remained unclear.

Purpose of the Study:

• To investigate the role of the Clock system, specifically Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), in osteoblasts.
• To determine how osteoblastic Clock system influences bone resorption and overall bone mass.
• To elucidate the molecular mechanisms by which osteoblastic Clock system modulates bone metabolism.

Main Methods:

• Analysis of Bmal1 and Per1 expression patterns in bone tissue and cultured osteoblasts.
• Generation and analysis of global Bmal1 knockout mice and osteoblast-specific Bmal1 knockout mice.
• Co-culture experiments to assess osteoclastogenesis.
• Measurement of receptor activator of nuclear factor κB ligand (Rankl) expression in response to 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3].

Main Results:

• Bmal1 and Per1 exhibited rhythmic expression in bone in vivo and in cultured osteoblasts.
• Global deletion of Bmal1 resulted in low bone mass and increased bone resorption.
• Osteoblast-specific deletion of Bmal1 recapitulated the low bone mass phenotype.
• Bmal1-deficient osteoblasts showed an enhanced capacity to support osteoclastogenesis.
• 1,25(OH)2D3-induced Rankl expression was significantly upregulated in Bmal1-deficient bone and osteoblasts.

Conclusions:

• The osteoblastic Clock system, particularly Bmal1, plays a critical role in regulating bone resorption and maintaining bone mass.
• Bmal1 deficiency in osteoblasts promotes bone resorption through enhanced Rankl expression, contributing to low bone mass.
• The findings reveal a sophisticated mechanism by which the circadian Clock system in osteoblasts influences skeletal homeostasis, partly via modulation of 1,25(OH)2D3-induced Rankl expression.