Compressive stress-driven mechanosignaling in chondrocytes: From molecular mechanism to scaffold engineering and translational opportunities.

Abstract

Articular cartilage, a unique avascular and low-cell-density connective tissue, relies predominantly on chondrocyte responses to mechanical cues for the maintenance of tissue homeostasis and functional repair. Among the diverse mechanical stimuli encountered in the joint microenvironment, compressive stress stands as the most prominent and physiologically relevant physical signal regulating chondrocyte behavior. This review systematically dissects the multi-layered mechanisms underlying compressive stress-mediated chondrocyte regulation and its translational implications in cartilage tissue engineering and osteoarthritis (OA) intervention. At the molecular level, compressive stress initiates a cascade of mechanosensing, intracellular transduction, and functional output through the synergistic crosstalk of integrin-mediated adhesion complexes, calcium signaling networks, MAPK pathways, and downstream transcriptional regulators (e.g., SOX9, Runx2, Sp1), which collectively orchestrate the balance between anabolic and catabolic metabolism. At the cellular level, articular cartilage's inherent regional heterogeneity, coupled with distinct responses of healthy/pathological chondrocytes and stem cells to compressive parameters (frequency, strain magnitude, loading mode, duration), underscores the need for cell-type-specific mechanical intervention strategies. At the translational level, moderate dynamic compression promotes cartilage repair by preserving extracellular matrix integrity, suppressing inflammatory cascades, and modulating epigenetic landscapes, while aberrant loading exacerbates OA progression via chondrocyte apoptosis, matrix degradation, and pain sensitization. The optimization of scaffold materials (natural polymers, synthetic composites, intelligent responsive matrices) and culture systems (3D bioprinting, microfluidic bioreactors, shear-compression synergistic loading) has emerged as a critical enabler to enhance mechanical regulation efficacy. Despite significant advances, current research is constrained by insufficiently physiological in vitro/in vivo models, lack of standardized loading parameters, unclear pathway crosstalk mechanisms, and limited clinical translation of mechanical-based therapies. Future endeavors should prioritize the elucidation of multi-pathway synergistic networks using multi-omics approaches, establishment of personalized mechanical parameter databases integrating patient-specific factors (age, gender, disease severity), construction of bionic models recapitulating the joint's dynamic microenvironment, and development of combined mechanical-biological therapeutic strategies. These efforts will provide more precise molecular targets and clinically feasible schemes for cartilage repair and OA management.