Meng Xiangbo, Qin Ling, Wang Xinluan
Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
University of Chinese Academy of Sciences, Beijing, PR China.
Bone Res. 2025 May 12;13(1):52. doi: 10.1038/s41413-025-00435-y.
Osteoarthritis (OA) is a prevalent degenerative joint disorder marked by chronic pain, inflammation, and cartilage loss, with current treatments limited to symptom relief. G protein-coupled receptors (GPCRs) play a pivotal role in OA progression by regulating inflammation, chondrocyte survival, and matrix homeostasis. However, their multifaceted signaling, via G proteins or β-arrestins, poses challenges for precise therapeutic targeting. Biased agonism, where ligands selectively activate specific GPCR pathways, emerges as a promising approach to optimize efficacy and reduce side effects. This review examines biased signaling in OA-associated GPCRs, including cannabinoid receptors (CB, CB), chemokine receptors (CCR2, CXCR4), protease-activated receptors (PAR-2), adenosine receptors (AR, AR, AR, AR), melanocortin receptors (MCR, MCR), bradykinin receptors (BR), prostaglandin E receptors (EP-2, EP-4), and calcium-sensing receptors (CaSR). We analyze ligands in clinical trials and explore natural products from Traditional Chinese Medicine as potential biased agonists. These compounds, with diverse structures and bioactivities, offer novel therapeutic avenues. By harnessing biased agonism, this review underscores the potential for developing targeted, safer OA therapies that address its complex pathology, bridging molecular insights with clinical translation.
骨关节炎（OA）是一种常见的退行性关节疾病，其特征为慢性疼痛、炎症和软骨丢失，目前的治疗方法仅限于缓解症状。G蛋白偶联受体（GPCRs）通过调节炎症、软骨细胞存活和基质稳态在OA进展中起关键作用。然而，它们通过G蛋白或β-抑制蛋白的多方面信号传导给精确的治疗靶点带来了挑战。偏向性激动作用，即配体选择性激活特定的GPCR途径，成为一种优化疗效和减少副作用的有前景的方法。这篇综述研究了OA相关GPCRs中的偏向性信号传导，包括大麻素受体（CB1、CB2）、趋化因子受体（CCR2、CXCR4）、蛋白酶激活受体（PAR-2）、腺苷受体（A1R、A2AR、A2BR、A3R）、黑皮质素受体（MC1R、MC4R）、缓激肽受体（B1R、B2R）、前列腺素E受体（EP-2、EP-4）和钙敏感受体（CaSR）。我们分析了临床试验中的配体，并探索了来自中药的天然产物作为潜在的偏向性激动剂。这些具有不同结构和生物活性的化合物提供了新的治疗途径。通过利用偏向性激动作用，这篇综述强调了开发针对OA复杂病理的靶向性更强、更安全的治疗方法的潜力，将分子见解与临床转化联系起来。
