膜上G蛋白偶联受体在运动影响骨代谢中的作用

Role of GPCRs in The Effect of Exercise on Bone Metabolism

膜上G蛋白偶联受体(GPCRs)是骨细胞感知外部信号刺激的关键跨膜蛋白,因其在成骨细胞(OB)、软骨细胞和破骨细胞(OC)分化和功能发挥上扮演的关键角色而在骨代谢研究领域备受关注。GPCRs功能缺失或异常升高后,骨细胞内环境稳态失衡,导致OB、软骨细胞和OC分化及代谢紊乱,骨组织微细结构退化。运动通过促进骨形成并抑制骨吸收来改善骨代谢,其机制与GPCRs(如GPR48、GPR54、GPR30等)介导的关键信号途径(cAMP/PKA/Atf4、JNK/AP-1、ERK1/2等)和细胞因子(T-PINP、Nkx3.2、Sox9和Cleaved-caspase-3等)调控下游级联反应来影响OB、软骨细胞和OC分化或功能密切相关。本文通过梳理GPCRs在运动改善骨代谢中的可能机制,有助于筛选出膜上敏感GPCRs来作为骨代谢疾病药物研发“效应器”以及运动干预中的力学刺激“明星蛋白”,为骨质疏松的研究和防治提供更多靶点或视角。

The bone formation metabolism dominated by osteoblasts(OB)has been restrained and the bone resorption metabolism dominated by osteoclasts(OC)is abnormally elevated,leading to bone metabolism disorders.As the key seven-transmembrane proteins that sense external signal stimuli in OBs,chondrocytes and OCs,G protein-coupled receptors(GPCRs)have been widely recognized by bone in their key regulatory roles in the differentiation and function of OBs,chondrocytes and OCs.Thus,those research results have got more attention in metabolism field.Loss of GPCRs function or abnormal increase in the homeostasis of the osteocyte homeostasis leads to the differentiation and dysfunction of OB,chondrocytes and OC,which results in bone loss and degeneration of the microstructure of bone tissue.Studies have shown that exercise is an important way to improve bone metabolism disorders by promoting bone formation and inhibiting bone resorption.The analysis found that the molecular regulation mechanism of this process is related to the key signaling pathways(cAMP/PKA/Atf4,JNK/AP-1,ERK1/2,etc.)and cytokines(T-PINP,Nkx3.2,Sox9 and Cleaved-caspase-3,etc.)are closely related to the differentiation and function of OB,chondrocytes and OC.Except from the confirmed GPR48,this review tested out the molecular mechanism of GPCRs regulating bone formation and bone resorption and their role in the effect of exercise on bone metabolism.The mechanism of other GPCRs in the improvement of bone metabolism by exercise has yet to be revealed on what kind of exercise mode and intensity can effectively regulate GPCR and improve bone metabolism and so on.The results help to screen out sensitive GPCRs on membranes as“effectors”for drug development of bone metabolic diseases and“star proteins”for mechanical stimulation in exercise intervention and provide more targets or perspectives for the research and prevention of osteoporosis.