title: Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype.
abstract: 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.
authors.affiliation: Center for Gene Regulation in Health and Diseases, BGES, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115-2214, USA. Electronic address: samsa.william@gmail.com.
authors.forename: William E
authors.initials: WE
authors.lastname: Samsa
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA. Electronic address: avasanji@image-iq.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Vasanji
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA. Electronic address: midurar@ccf.org.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Midura
authors.affiliation: Center for Gene Regulation in Health and Diseases, BGES, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115-2214, USA. Electronic address: r.kondratov@csuohio.edu.
authors.forename: Roman V
authors.initials: RV
authors.lastname: Kondratov
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency* / Q000378:metabolism*; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D002454:Cell Differentiation; D057906:Circadian Clocks; D004838:Epiphyses / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010011:Osteocytes / Q000473:pathology; D010641:Phenotype; D055114:X-Ray Microtomography
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse
keywords: Aging; Biological clock; Mesenchymal stem cell; Osteoblast; Osteogenesis, bone