BMAL1 deficiency promotes skeletal mandibular hypoplasia via OPG downregulation

Aug 18, 2018Cell proliferation

Lack of BMAL1 may cause underdeveloped jaw bone by lowering bone-protecting protein levels

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Abstract

BMAL1 deficiency is associated with decreased expression of OPG and increased osteoclast differentiation, contributing to skeletal mandibular hypoplasia (SMH).

Expressions of BMAL1 and OPG are reduced in patients with SMH.
Circadian rhythm-disordered mice and mice lacking BMAL1 showed decreased OPG levels, leading to reduced bone mass and size in the mandibles.
BMAL1 directly binds to the Opg promoter to enhance its expression, which inhibits the formation of osteoclasts.
A decrease in OPG expression due to BMAL1 deficiency may lead to increased osteoclast differentiation.
Supplementation with OPG can significantly reverse the effects of BMAL1 knockdown on osteoclast differentiation.

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OBJECTIVES: Skeletal mandibular hypoplasia (SMH), a common type of developmental deformities, results in impaired aesthetics of facial profile, occlusal dysfunction and poor life quality. In this study, BMAL1 deficiency leads to SMH formation, and we aim to investigate the mechanism by which BMAL1 deficiency induces SMH.

MATERIALS AND METHODS: Circadian rhythm-disordered mouse models were constructed by placing animals in a jet lag schedule of 6-h light advance every 7 days for 4 or 8 weeks. The OPG expression was evaluated by histomorphometry, immunohistochemistry and western blot analysis. The mechanism by which BMAL1 affects OPG expression was investigated by chromatin immunoprecipitation and luciferase reporter assays. The phenotypes caused by BMAL1 knockout can be rescued by exogenous supplementation with OPG.

RESULTS: We demonstrate that the expressions of BMAL1 and OPG decreased in SMH patients. Circadian rhythm-disordered mice and Bmal1mice exhibited decreased expression of OPG, reduced bone mass and bone size of mandibles. Our results revealed that BMAL1 bound directly to the Opg promoter and upregulated its expression, thus inhibiting osteoclast differentiation. BMAL1 deficiency increased osteoclast differentiation by downregulating OPG expression. In vitro, the enhancement effect of osteoclast differentiation caused by BMAL1 knockdown was significantly reversed by exogenous supplementation with OPG. Importantly, bone loss caused by BMAL1 knockout can be partially reversed by injecting OPG Intraperitoneally. -/-

CONCLUSIONS: These results indicate that the circadian clock plays a critical role in the growth and development of mandible by regulating OPG expression, and present a potential therapeutic strategy to prevent SMH.

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BMAL1 deficiency promotes skeletal mandibular hypoplasia via OPG downregulation

Abstract

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