The mechanobiology of extracellular matrix: a focus on thrombospondins

Abstract

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.

Keywords: Cardiovascular system; Extracellular matrix; Fibrotic tissues; Mechano-transduction; Musculoskeletal system; Thrombospondins; Tumors.

Fig. 1

Structural classification of the TSP family proteins. (A) Molecular architecture of TSP-1 and − 2; (B) Molecular architecture of TSP-3, -4 and − 5; (C) Proteins interacting with distinct structural domains of TSPs

Fig. 2

Mechanical stimuli-dependent TSP signaling in cardiovascular remodeling (A) TSP-1-CD47 binding activates platelet αIIβ3 integrin to mediate endothelial adhesion through fibrinogen bridging with ICAM-1/αvβ3 under shear stress. (B) Cyclic stretch induces TSP-1 secretion in SMCs, which binds αvβ1 integrin to promote FA-actin maturation and YAP nuclear translocation via Rap2/Hippo inactivation. (C) Disturbed flow induces TSP-1/integrin/CD47 complex formation or activates the TSP-1–TGF-β axis, driving collagen deposition and atherosclerotic plaque progression. (D) Shear stress induces TSP-1-mediated platelet aggregation and endothelial adhesion via the CD36/integrin αIIβ3–Syk axis and TSP-1–GPIb/IIbIIIa interactions

Fig. 3

Mechanical stimuli-dependent TSPs signaling in musculoskeletal remodeling (A) Mechanical loading activates the YAP/TAZ–TSP-1 axis in mesenchymal progenitors, driving CD47-mediated MuSC proliferation and fusion to promote muscle hypertrophy. (B) TSP-1 mediates mechanical responses via CD47/integrin α5β1 interactions in cartilage. (C) Pressure upregulates TSP-2 in BMSCs to synergistically activate the NF-κB pathway, driving chondrogenesis. (D) Mechanical loading activates periosteal myeloid cells, driving TSP-1 expression, which triggers TGF-β1-dependent osteoprogenitor recruitment

Fig. 4

TSPs orchestrate mechanosensitive signaling networks in fibrotic and neoplastic microenvironments via matrix stiffness remodeling (A) The TSP-2 dimer engages TLR4 in hepatic fibrosis to activate profibrotic FAK/TGF-β signaling in HSCs, with axis disruption attenuating fibrotic progression. (B) TSP-1 promotes liver fibrosis via CD47-mediated Rho/ROCK pathway activation. (C) Mechanical stress upregulates TSP-1 in the spinal ligamentum flavum, activating TGF-β1/Smad signaling to increase COL1A2/α-SMA expression and drive hypertrophic fibrosis. (D) Matrix stiffening upregulates CAF-derived TSP-1 in PDAC, activating TGF-β/Smad-Akt signaling to drive tumor proliferation/EMT, whereas TSP-1 silencing attenuates stromal activation and the expression of profibrotic markers