Soft tissue mechanosensing and remodeling: the core regulatory role of Piezo/TRPV4 ion channels

Soft tissue fibrosis and chronic pain involve a cycle linking extracellular matrix (ECM) stiffening, inflammation, and neural sensitization. This review develops a multiscale framework that spans from molecular mechanisms to organ-level physiology and focuses on the directly mechanosensitive Piezo1/2 channels and the mechano-responsive TRPV4 channel, drawing on their distinct molecular architectures to ground divergent gating properties. We examine how these channels convert membrane tension and integrin-mediated traction into Ca²⁺ and other ionic signals that, together with Ca²⁺-independent pathways engage YAP/TAZ, NF-κB, and TGF-β pathways, thereby reshaping transcriptional programs. We then conceptualize healthy ECM as a "spatial filter," noting that viscoelasticity and non-affine fiber rearrangements buffer superficial loads, whereas fibrotic cross-linking erodes this protection, chronically exposing fibroblasts and sensory endings to elevated mechanical and inflammatory cues. This may drive pathological "stiffness-inflammation-fibrosis/pain" loops. Finally, we propose a mechanical therapeutic window in which mechanical interventions, parameterized by channel modulation and/or viscoelastic biomaterials, reset the local environment toward a near-physiological state. Within this Goldilocks zone, reparative and inflammation-resolving pathways can be preferentially engaged while minimizing damage and pain amplification. This integrated perspective offers a conceptual framework for understanding fibrosis-associated disorders and chronic soft-tissue pain, and may inform therapies targeting Piezo/TRPV4 signaling and ECM viscoelasticity.