Zhang Yan, Wang Nai-Ning, Qiu Zi-Han, Wang Jia-Hao, An Wen-Na, Shi Li-Dan, Chen Fei, Zhang Da-Jin, Wang Si-Yue, Yang Tie-Lin, Hu Shou-Ye, Guo Yan
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, and Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.
Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710054, China.
Int J Biol Sci. 2025 Jul 24;21(11):4736-4761. doi: 10.7150/ijbs.113585. eCollection 2025.
G protein-coupled receptors (GPCRs) are recognized as critical therapeutic targets in bone disorders, owing to their multifaceted regulatory roles across diverse bone cell lineages. This review systematically catalogs GPCR expression and functional heterogeneity in key bone cells: 12 GPCRs in mesenchymal stem cells (MSCs) orchestrate lineage specification; 21 GPCRs in osteoblasts/osteocytes mediate matrix mineralization and mechanotransduction; 23 GPCRs in macrophages/osteoclasts regulate inflammatory bone resorption; 31 GPCRs in chondrocytes govern endochondral ossification and osteoarthritis pathogenesis; and 8 GPCRs in other cell types modulate bone-related physiological processes. By integrating canonical signaling axes-cAMP/PKA-dependent transcriptional networks, PLC-β/IP3-driven calcium signaling, and NF-κB-modulated immuno-skeletal interactions-we elucidate how GPCRs dynamically coordinate cellular plasticity to maintain skeletal homeostasis. This work establishes a multidimensional research framework integrating historical context, molecular mechanisms, and cutting-edge methodologies to advance GPCR-targeted therapies for bone-related diseases. Moreover, this review provides insights for clinical translation, including biased agonism and allosteric modulation precision strategies to restore skeletal equilibrium in osteoporosis, arthritis, and regenerative medicine.
G蛋白偶联受体（GPCRs）因其在多种骨细胞谱系中具有多方面的调节作用，而被认为是骨疾病中的关键治疗靶点。本综述系统梳理了关键骨细胞中GPCR的表达情况和功能异质性：间充质干细胞（MSCs）中的12种GPCR协调谱系分化；成骨细胞/骨细胞中的21种GPCR介导基质矿化和机械转导；巨噬细胞/破骨细胞中的23种GPCR调节炎症性骨吸收；软骨细胞中的31种GPCR控制软骨内成骨和骨关节炎发病机制；其他细胞类型中的8种GPCR调节与骨相关的生理过程。通过整合经典信号轴——cAMP/PKA依赖性转录网络、PLC-β/IP3驱动的钙信号以及NF-κB调节的免疫-骨骼相互作用——我们阐明了GPCR如何动态协调细胞可塑性以维持骨骼稳态。这项工作建立了一个多维研究框架，整合了历史背景、分子机制和前沿方法，以推进针对骨相关疾病的GPCR靶向治疗。此外，本综述为临床转化提供了见解，包括偏向性激动和变构调节精准策略，以恢复骨质疏松症、关节炎和再生医学中的骨骼平衡。
