Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype

Jan 21, 2016Bone

Lack of the daily rhythm protein BMAL1 leads to low bone mass in mice

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Abstract

Bmal1(-/-) mice exhibit a low bone mass phenotype that worsens with age.

Deficiency of BMAL1 leads to accelerated aging and age-associated pathologies.
Bone mass loss in Bmal1(-/-) mice is progressive, beginning after birth.
Formation of bony bridges between the metaphysis and epiphysis results in shorter long bones.
Micro-computed tomography reveals decreased cortical and trabecular bone volume and lower bone mineral density in Bmal1(-/-) mice.
Histological analysis shows fewer active bone-forming cells, osteoblasts and osteocytes, in mice lacking BMAL1.
Bone marrow-derived stem cells from Bmal1(-/-) mice have a reduced capacity to become osteoblasts, which may contribute to decreased bone density.

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The circadian clock is an endogenous time keeping system that controls the physiology and behavior of many organisms. The transcription factor Brain and Muscle ARNT-like Protein 1 (BMAL1) is a component of the circadian clock and necessary for clock function. Bmal1(-/-) mice display accelerated aging and many accompanying age associated pathologies. Here, we report that mice deficient for BMAL1 have a low bone mass phenotype that is absent at birth and progressively worsens over their lifespan. Accelerated aging of these mice is associated with the formation of bony bridges occurring across the metaphysis to the epiphysis, resulting in shorter long bones. Using micro-computed tomography we show that Bmal1(-/-) mice have reductions in cortical and trabecular bone volume and other micro-structural parameters and a lower bone mineral density. Histology shows a deficiency of BMAL1 results in a reduced number of active osteoblasts and osteocytes in vivo. Isolation of bone marrow derived mesenchymal stem cells from Bmal1(-/-) mice demonstrate a reduced ability to differentiate into osteoblasts in vitro, which likely explains the observed reductions in osteoblasts and osteocytes, and may contribute to the observed osteopenia. Our data support the role of the circadian clock in the regulation of bone homeostasis and shows that BMAL1 deficiency results in a low bone mass phenotype.

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Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype

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