Zhao Ying, Lei Ting, Ge Xin, Fan Liumeizi, He Yinbin, Yu Zhou, Hu Sheng
Department of Anesthesiology and Perioperative Medicine, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University, Xi'an, Shaanxi Province, China.
Department of Stomatology, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University, Xi'an, Shaanxi, China.
Cell Commun Signal. 2025 Jul 25;23(1):354. doi: 10.1186/s12964-025-02365-y.
Mechanosensitive thrombospondins (TSPs), a class of extracellular matrix (ECM) glycoproteins, have garnered increasing attention for their pivotal roles in transducing mechanical cues into biochemical signals during tissue adaptation and disease progression. This review delineates the context-dependent functions of TSP isoforms in cardiovascular homeostasis maintenance, cardiovascular remodeling, musculoskeletal adaptation, and pathologies linked to ECM stiffening, including fibrosis and tumorigenesis. Mechanistically, biomechanical stimuli regulate the expression of TSPs, enabling their interaction with transmembrane receptors and the activation of downstream effectors to orchestrate cellular responses. Under physiological mechanical stimuli, TSP-1 exhibits low-level expression, contributing to the maintenance of cardiovascular homeostasis. Conversely, under pathological mechanical stimuli, upregulated TSP-1 expression activates downstream signaling pathways. This leads to aberrant migration, proliferation, adhesion of cardiovascular cells, and collagen deposition, ultimately resulting in diseases including but not limited to atherosclerosis, pulmonary arterial hypertension (PAH), and myocardial fibrosis. In load-bearing musculoskeletal tissues, TSP-1 facilitates the mechanical adaptation of skeletal muscle and promotes cortical bone formation, whereas TSP-2 regulates chondrogenic differentiation. Within fibrotic and neoplastic tissues characterized by altered matrix stiffness, TSP-1 and - 2 exacerbates tissue fibrosis and tumor progression through transforming growth factor-β (TGF-β)-mediated signaling pathways. These findings establish TSPs as critical mechanochemical switches that govern tissue homeostasis and maladaptation. Clinically, the isoform-specific expression patterns of TSPs correlate with disease severity in atherosclerosis, osteoarthritis, and fibrotic tissues, highlighting their potential as mechanobiological biomarkers. Therapeutically, targeting force-sensitive TSP-receptor interfaces or mimicking their conformational changes under mechanical loading offers innovative strategies for treating mechanopathologies. This review provides a framework for understanding TSP-mediated mechanotransduction across scales, bridging molecular insights for translational applications in mechanopharmacology and ECM-targeted regenerative therapies.
机械敏感的血小板反应蛋白（TSPs）是一类细胞外基质（ECM）糖蛋白，因其在组织适应和疾病进展过程中将机械信号转化为生化信号方面的关键作用而受到越来越多的关注。本综述阐述了TSP亚型在维持心血管稳态、心血管重塑、肌肉骨骼适应以及与ECM硬化相关的病理过程（包括纤维化和肿瘤发生）中的上下文依赖性功能。从机制上讲，生物力学刺激调节TSPs的表达，使其能够与跨膜受体相互作用并激活下游效应器，从而协调细胞反应。在生理机械刺激下，TSP-1表达水平较低，有助于维持心血管稳态。相反，在病理机械刺激下，TSP-1表达上调会激活下游信号通路。这导致心血管细胞异常迁移、增殖、黏附以及胶原蛋白沉积，最终导致包括但不限于动脉粥样硬化、肺动脉高压（PAH）和心肌纤维化等疾病。在承重的肌肉骨骼组织中，TSP-1促进骨骼肌的机械适应并促进皮质骨形成，而TSP-2调节软骨生成分化。在以基质硬度改变为特征的纤维化和肿瘤组织中，TSP-1和-2通过转化生长因子-β（TGF-β）介导的信号通路加剧组织纤维化和肿瘤进展。这些发现确立了TSPs作为控制组织稳态和适应不良的关键机械化学开关。临床上，TSPs的亚型特异性表达模式与动脉粥样硬化、骨关节炎和纤维化组织中的疾病严重程度相关，突出了它们作为机械生物学生物标志物的潜力。在治疗方面，靶向力敏感的TSP-受体界面或模拟它们在机械负荷下的构象变化为治疗机械性疾病提供了创新策略。本综述提供了一个框架，用于理解跨尺度的TSP介导的机械转导，为机械药理学和ECM靶向再生疗法的转化应用提供分子见解。
