Department of Orthopaedic Surgery, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2020 Nov 10;11:583105. doi: 10.3389/fendo.2020.583105. eCollection 2020.
Inhibition of neuropeptide Y1 receptor stimulates osteogenesis and . However, the underlying mechanisms involved in these effects remain poorly understood. Here we identify the effects of Y1 receptor deficiency on osteogenic differentiation in human bone marrow stromal cells (BMSCs) by using genetic and pharmacological regulation, and to explore the pathways mediating these effects. In BMSCs, inhibition of Y1 receptor stimulates osteogenesis and upregulates the expression levels of the master transcriptional factor RUNX2. Mechanistically, Y1 receptor deficiency increases the levels of intracellular cAMP, which protein kinase A (PKA) mediated pathways results in activation of phospho-CREB (p-CREB). We find RUNX2 activation induced by Y1 receptor deficiency is reversed by H-89, a PKA inhibitor. These results indicate Y1 receptor deficiency activates PKA-mediated phosphorylation of CREB, leading to activation of RUNX2 and enhances osteogenic differentiation in BMSCs. In conclusion, these data indicate that Y1 receptor deficiency promotes osteogenic differentiation by RUNX2 stimulation through cAMP/PKA/CREB pathway.
神经肽 Y1 受体抑制物可刺激成骨作用和骨形成。然而，这些作用的潜在机制仍知之甚少。在这里，我们通过遗传和药理学调节，确定了 Y1 受体缺乏对人骨髓基质细胞（BMSCs）成骨分化的影响，并探讨了介导这些作用的途径。在 BMSCs 中，Y1 受体抑制物刺激成骨作用并上调主转录因子 RUNX2 的表达水平。在机制上，Y1 受体缺乏会增加细胞内 cAMP 的水平，从而导致蛋白激酶 A（PKA）介导的途径激活磷酸化 CREB（p-CREB）。我们发现 Y1 受体缺乏诱导的 RUNX2 激活可被 PKA 抑制剂 H-89 逆转。这些结果表明，Y1 受体缺乏通过 cAMP/PKA/CREB 途径激活 PKA 介导的 CREB 磷酸化，从而激活 RUNX2 并增强 BMSCs 中的成骨分化。总之，这些数据表明，Y1 受体缺乏通过 cAMP/PKA/CREB 途径刺激 RUNX2 促进成骨分化。
