Background/Objectives: Osteoarthritis (OA) is an age-related degenerative joint disease whose pathogenic mechanisms remain poorly understood. Experimental evidence implicates dysregulated mechanotransduction mediated by Piezo1 and TRPV4 channels, but how their interaction with inflammation may drive pathogenic state transitions remains unknown. Here, we aimed to study whether a Piezo1–TRPV4 network can intrinsically produce distinct stable physiological and pathological regimes. Methods: Based on literature data, we developed a nonlinear dynamical model describing closed-loop interactions involving Piezo1, TRPV4, and inflammation. The system was translated into a set of ordinary differential equations and studied using stability and bifurcation analysis. Results: Computational analysis revealed bistability, allowing the system to shift from a physiological to a pathogenic regime in response to specific stimuli. Critical bifurcation parameters were linked to Piezo1 and inflammation, suggesting that the bidirectional interaction between these two components represents a key node for interventions aimed at preventing or reversing transitions from non-pathogenic to pathogenic states. Conclusions: Our results suggest that OA pathogenesis may emerge from the intrinsic nonlinear dynamics of Piezo1/TRPV4/inflammation interactions. Bifurcation analysis indicates the sensitivity of TRPV4 to the inhibitory effect of Piezo1 as a key target for preventing or reversing pathogenic state transitions. Further investigations in preclinical and clinical settings are warranted to validate the model.
Burlando et al. (2026) studied this question.