BMAL1 regulates balance of osteogenic–osteoclastic function of bone marrow mesenchymal stem cells in type 2 diabetes mellitus through the NF-κB pathway

Sep 28, 2018Molecular biology reports

BMAL1 controls bone-building and bone-breaking balance in bone stem cells in type 2 diabetes through the NF-κB pathway

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Abstract

In diabetic bone marrow mesenchymal stem cells (BMSCs), BMAL1 overexpression improved osteogenesis and suppressed osteoclast activity.

Type 2 diabetes mellitus (T2DM) leads to metabolic and functional disorders in BMSCs, causing an imbalance in bone resorption and formation.
In diabetic BMSCs, the ratio of receptor activator of nuclear factor-κB ligand to osteoprotegerin (RANKL/OPG) is increased.
Expression levels of Inhibitor κB (IκB) are decreased, while phosphorylated-p65, caspase-3, and phosphorylated IκB are increased in diabetic BMSCs.
Overexpression of BMAL1 in diabetic BMSCs enhances their osteogenesis capacity and reduces osteoclastic induction.
The effects of BMAL1 overexpression may be linked to the partial inhibition of NF-κB pathway activity.
These findings suggest a potential approach to restore bone metabolism homeostasis in T2DM by targeting BMAL1.

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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.

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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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