Mechanical sensing of fluid shear stress biphasically regulates chondrocyte metabolism and osteoarthritis...

Articular cartilage homeostasis relies on chondrocytes to maintain extracellular matrix (ECM) integrity, with fluid shear stress (FSS) emerging as a critical regulator of chondrocyte function. Osteoarthritis (OA), a leading cause of global disability, is driven by abnormal mechanical loading, yet the dual role of FSS in joint health and disease remains incompletely defined, and existing reviews have not fully integrated its biphasic dose-effect boundaries, mechanotransduction networks, and translational pathways within a unified framework. To address this gap, we synthesize evidence that FSS exerts biphasic control over chondrocyte biology: physiological FSS, operationally approximated as low-to-moderate laminar shear stress within 0.5-10 Pa in many in vitro models, sustains cartilage homeostasis via anabolic pathways (ERK5, PI3K/Akt, AMPK) that promote ECM synthesis, cell proliferation, and cytoprotection; in contrast, pathological FSS, often exceeding approximately 10-15 Pa or occurring as prolonged continuous/turbulent shear or under inflammatory conditions, triggers catabolic and pro-inflammatory responses (NF-κB, JNK, Hippo/YAP) recapitulating OA phenotypes, including ECM degradation and chondrocyte apoptosis. Mechanotransduction of FSS involves conserved sensors (Ca²⁺ channels, integrins, cytoskeleton) and extensive crosstalk between signaling networks and additional regulation by non-coding RNAs, thereby providing an integrated mechanosensory-to-transcriptional framework for interpreting FSS-dependent chondrocyte responses. Translating this duality, FSS-based strategies, from tissue engineering bioreactors to targeted inhibition of pathological pathways and mechanical interventions, hold promise for OA therapy, providing an integrated framework for clinical translation. However, context dependency of FSS effects, microenvironmental heterogeneity, and signaling redundancy remain barriers to clinical translation. Resolving these challenges via biomimetic models and multidisciplinary approaches will advance precision medicine for OA by harnessing FSS's therapeutic potential while mitigating its pathological contributions.