BMAL1 regulates balance of osteogenic–osteoclastic function of bone marrow mesenchymal stem cells in type 2 diabetes mellitus through the NF-κB pathway
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In bone marrow mesenchymal stem cell (BMSCs), type 2 diabetes mellitus (T2DM) induces metabolic and functional disorders, leading to imbalanced bone resorption and formation and bone loss. Brain and muscle ARNT-like protein 1 (BMAL1) is involved in regulating T2DM-related suppression of BMSCs osteogenesis and bone formation. However, the relationship between BMAL1 and bone remodelling, especially bone resorption in T2DM, is unclear. We investigated the antergic role played by BMAL1 in T2DM-prompted imbalance in BMSCs osteogenic–osteoclastic function. BMAL1 was inhibited and the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio was increased in diabetic BMSCs. Inhibitor κB (IκB) expression was decreased, whereas phosphorylated-p65 (p-p65), caspase-3, and p-IκB expression were increased in diabetic BMSCs. BMAL1 overexpression recovered the osteogenesis ability and suppressed osteoclastic induction capability of BMSCs to improve bone metabolism and function, which was partially due to NF-κB pathway activity inhibition. Our results provide evidence about the role of BMAL1 in T2DM-prompted BMSCs differentiation dysfunction, i.e. partially decreasing NF-κB pathway expression. In T2DM, it might be possible to use overexpressed BMAL1 to re-establish the homeostasis of bone metabolism.
KeywordsBone marrow mesenchymal stem cells Osteoclast induction Osteogenic differentiation Brain and muscle ARNT-like protein 1 Nuclear factor-κB Type 2 diabetes mellitus
This work was supported by the National Natural Science Foundation of China (81470754, 51473175, and 31670998); and the Beijing Nova program (Z141107001814101). We thank the staff of the Technical Institute of Physics and Chemistry CAS for their support.
LX, LN, ZD, and GB designed and analyzed data. LX, HW, and LY performed the experiments. LX, LN, GB, and ZD interpreted the results. LX drafted the manuscript. All the authors approved the final version of manuscript. All authors certify that we have participated sufficiently in the work to take public responsibility for the appropriateness of the collection, analysis, and interpretation of the data. All authors have contributed significantly and are in agreement with the content of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest with respect to the authorship and/or publication of this article.
We performed all experiments in accordance with the National Institutes of Health (NIH, Bethesda, MD, USA) Guidelines for the Care and Use of Laboratory Animals; the PLA General Hospital Institutional Animal Care and Use Committee of approved the experiments (2015-x10-38).
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