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

## TL;DR

Excessive mechanical stress worsens knee osteoarthritis by activating a specific signaling pathway in bone cells, leading to abnormal bone remodeling and cartilage damage.

## Contribution

The study identifies the Piezo1-Ca²⁺-JAK2/STAT3 signaling axis as a novel mechanism linking mechanical overload to knee osteoarthritis progression.

## Key findings

- Mechanical overload activates Piezo1 in osteoblasts, promoting Ca²⁺ influx and bone sclerosis.
- Blocking the Piezo1-JAK2/STAT3 pathway reduces subchondral bone changes and cartilage degeneration in mice.
- Osteoblast-specific deletion of JAK2 mitigates KOA progression in vivo.

## Abstract

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 in vitro 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 in vivo. 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.