Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Trauma and Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Front Endocrinol (Lausanne). 2024 Sep 19;15:1392418. doi: 10.3389/fendo.2024.1392418. eCollection 2024.
Bone is a dynamic tissue that is constantly remodeled throughout adult life. Recently, it has been shown that bone turnover decreases shortly after food consumption. This process has been linked to the fermentation of non-digestible food ingredients such as inulin by gut microbes, which results in the production of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate. SCFAs exert various metabolic functions, which in part can be explained by activation of G protein-coupled receptors (Gpr) 41 and 43. However, the potential relevance of a SCFA-Gpr41/43 signaling axis for bone metabolism has not been established. The aim of our study is to investigate the role of Gpr41/43 in bone metabolism and osteogenic differentiation of mesenchymal stem cells. For this purpose, we analyzed the skeletal phenotype of wild type controls (WT) and Gpr41/43 double knockout (Gpr41/43 dKO) mice fed either a chow or an inulin-enriched diet. In addition, we isolated bone marrow derived mesenchymal stem cells from WT and Gpr41/43 dKO mice and differentiated them into osteoblasts in the absence or presence of acetate. MicroCT scanning of femoral bones of Gpr41/43 dKO mice revealed a significant increase of trabecular bone volume and trabecular compared to WT controls. Treatment of WT bone marrow-derived osteoblasts with acetate resulted in decreased mineralization and substantial downregulation of bone formation markers such as , and . Notably, this effect was strongly attenuated in differentiated osteoblasts lacking Gpr41/43. Inversely, acetate supplementation resulted in higher levels of adipocyte marker genes including , and in bone marrow-derived cells from WT mice, an effect blunted in differentiated cells isolated from Gpr41/43 dKO mice. Overall, these data indicate that acetate regulates bone architecture via SCFA-Gpr41/43 signaling by modulating the osteogenic versus adipogenic differentiation of mesenchymal stem cells.
骨骼是一种在成人期不断重塑的动态组织。最近，人们发现进食后骨转换会短暂下降。这个过程与肠道微生物发酵不可消化的食物成分（如菊粉）有关，导致短链脂肪酸（SCFA）乙酸盐、丙酸盐和丁酸盐的产生。SCFAs 发挥着各种代谢功能，部分可以通过激活 G 蛋白偶联受体（Gpr）41 和 43 来解释。然而，SCFA-Gpr41/43 信号轴对骨代谢的潜在相关性尚未确定。我们的研究旨在探讨 Gpr41/43 在骨代谢和间充质干细胞成骨分化中的作用。为此，我们分析了饲喂标准饮食或富含菊粉饮食的野生型对照（WT）和 Gpr41/43 双敲除（Gpr41/43 dKO）小鼠的骨骼表型。此外，我们从 WT 和 Gpr41/43 dKO 小鼠中分离骨髓间充质干细胞，并在有无乙酸盐的情况下将其分化为成骨细胞。Gpr41/43 dKO 小鼠股骨的 microCT 扫描显示，与 WT 对照相比，骨小梁体积和骨小梁明显增加。WT 骨髓源性成骨细胞用乙酸盐处理导致矿化减少和骨形成标志物如 、 和 的显著下调。值得注意的是，在缺乏 Gpr41/43 的分化成骨细胞中，这种作用被强烈减弱。相反，乙酸盐补充导致 WT 小鼠骨髓源性细胞中包括 、 和 在内的脂肪细胞标志物基因水平升高，在从 Gpr41/43 dKO 小鼠分离的分化细胞中，这种作用减弱。总的来说，这些数据表明，乙酸盐通过 SCFA-Gpr41/43 信号调节骨架构，通过调节间充质干细胞的成骨与成脂分化。
