Abnormal mechanical load aggravates subchondral bone remodeling and uneven tibial plateau settlement in knee osteoarthritis via activation of osteoblast Piezo1-Ca²⁺-JAK2/STAT3 signaling

Mechanical overload is closely associated with the theory of uneven tibial plateau settlement in knee osteoarthritis (KOA). Excessive mechanical stress leads to abnormal force distribution within the subchondral bone, eventually inducing medial tibial plateau collapse. This process disrupts local biomechanical homeostasis and triggers aberrant bone remodeling. However, the precise molecular basis of subchondral bone remodeling and structural changes in the knee is still not fully understood. In this work, we employed a mouse model of KOA with osteoblast-specific Piezo1 deletion, together with <i>in vitro</i> loading experiments, to demonstrate that mechanical overload activates Piezo1, promotes Ca²⁺ influx, and drives osteoblast differentiation, thereby contributing to subchondral bone sclerosis. Mechanistic investigations revealed that inhibition of the Piezo1-JAK2/STAT3 signaling axis alleviated abnormal osteoblast activation and significantly ameliorated subchondral bone sclerosis and cartilage degeneration. Moreover, deletion of JAK2 in osteoblasts further confirmed that blockade of this pathway mitigates KOA progression <i>in vivo</i>. Collectively, our findings identify the Piezo1-Ca²⁺-JAK2/STAT3 axis as a key mediator of osteoblast mechanotransduction under pathological loading and a potential therapeutic target for mechanical overload-associated KOA.