MicroRNA-mediated mechanotransduction and chondrocyte differentiation in mesenchymal stem cells.

Abstract

Mesenchymal stem cells (MSCs) integrate mechanical information from their microenvironment to regulate lineage commitment. Through integrin-based adhesion, cytoskeletal tension, and nuclear deformation, mechanical cues are transduced into intracellular signals via conserved pathways such as integrin-FAK/Src, RhoA-ROCK, and Hippo-YAP/TAZ. These pathways not only regulate chromatin accessibility and transcriptional output but also induce characteristic changes in mechanosensitive microRNAs (miRNAs). Mechanical loading alters miRNA expression programs that modulate focal adhesion assembly, Rho GTPase activity, and SMAD or Wnt signaling, thereby refining the SOX9-centered transcriptional networks that drive MSC chondrogenesis. Physiological mechanical stimuli including dynamic compression, fluid shear, and controlled tensile strain promote chondrogenic differentiation by lowering actomyosin tension, restricting YAP/TAZ nuclear localization, and enhancing SMAD-SOX9 cooperation. Conversely, pathological changes in the pericellular matrix, such as reduced stiffness and increased permeability, disrupt mechanical filtering, impair force transmission, and destabilize cytoskeletal organization. These mechanical defects shift chondrocytes toward high-tension, YAP-active states that suppress matrix gene expression and hinder maintenance of the chondrogenic phenotype. Simultaneously, dysregulation of mechanosensitive miRNAs weakens negative regulation of inflammatory and catabolic pathways, contributing to extracellular matrix degradation and progressive cartilage degeneration. Although numerous mechanosensitive miRNAs have been identified, their mechanistic roles and context-specific regulation remain incompletely defined. A deeper understanding of how miRNAs integrate diverse mechanical cues is essential to elucidate MSC fate transitions and the mechanobiology of cartilage repair. Advances in single-cell mechanobiology, mechanically tunable culture systems, and miRNA-targeted modulation may ultimately yield diagnostic indicators of mechanical imbalance and new therapeutic strategies for restoring cartilage homeostasis.