Abstract
Free fatty acids display diverse effects as signalling molecules through GPCRs in addition to their involvement in cellular metabolism. GPR120, a G protein-coupled receptor for long-chain unsaturated fatty acids, has been reported to mediate adipogenesis in lipid metabolism. However, whether GPR120 also mediates osteogenesis and regulates BMMSCs remain unclear. In this study, we showed that GPR120 targeted the bi-potential differentiation of BMMSCs in a ligand dose-dependent manner. High concentrations of TUG-891 (a highly selective agonist of GPR120) promoted osteogenesis via the Ras-ERK1/2 cascade, while low concentrations elevated P38 and increased adipogenesis. The fine molecular regulation of GPR120 was implemented by up-regulating different integrin subunits (α1, α2 and β1; α5 and β3). The administration of high doses of TUG-891 rescued oestrogen-deficient bone loss in vivo, further supporting an essential role of GPR120 in bone metabolism. Our findings, for the first time, showed that GPR120-mediated cellular signalling determines the bi-potential differentiation of BMMSCs in a dose-dependent manner. Additionally, the induction of different integrin subunits was involved in the cytoplasmic regulation of a seesaw-like balance between ERK and p38 phosphorylation. These findings provide new hope for developing novel remedies to treat osteoporosis by adjusting the GPR120-mediated differentiation balance of BMMSCs.
Highlights
Osteoporosis (OP) is characterized by a decrease in bone mass and density accompanied by a dramatic change in the osteoblast/adipocyte ratio in the bone marrow cavity[1,2]
We detected the expression of GPR120 transcripts in primary bone marrow mesenchymal stem cells (BMMSCs) and found that the expression level of GPR120 was gradually increased during osteogenic induction
The potential of osteoblast differentiation of these BMMSCs was evaluated by Alkaline phosphatase (ALP) and Alizarin Red staining in the presence or absence of 50 μ M TUG-891, which is a highly selective agonist of GPR12029
Summary
Osteoporosis (OP) is characterized by a decrease in bone mass and density accompanied by a dramatic change in the osteoblast/adipocyte ratio in the bone marrow cavity[1,2]. The abnormal osteoblast/adipocyte ratio is determined by the imbalance between the decreased osteogenic and increased adipogenic differentiation tendency of bone marrow mesenchymal stem cells (BMMSCs)[3], and this imbalance will cause more fat to reside in the bone marrow cavity, which in turn modulates the bone formation process, causing osteoporosis[4]. Many core factors, such as β -catenin, Runx[2] and Ppar-γ , are highly involved in the bi-potential differentiation process of BMMSCs5–7; little evidence has shown how BMMSCs sense the extracellular signals and change their differentiation tendency in the first place. We speculated that GPR120 might be the “button” to modulate osteogenesis as well as GPR120-mediated adipogenesis of BMMSCs, and these two events might be underway through different molecular mechanisms
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