Excessive mechanical loading promotes osteoarthritis development by upregulating Rcn2.

Area of Science:

• Biomedical Engineering
• Cell Biology
• Orthopedics

Background:

• Osteoarthritis (OA) pathogenesis is linked to excessive mechanical loading of articular cartilage, but molecular mechanisms remain unclear.
• Understanding how mechanical forces impact chondrocytes is crucial for developing effective OA treatments.

Purpose of the Study:

• To identify novel mechanosensitive factors involved in OA pathogenesis.
• To elucidate the role of reticulocalbin-2 (Rcn2) in excessive mechanical loading-induced OA.
• To investigate the molecular mechanism by which Rcn2 influences OA progression.

Main Methods:

• In vitro: Primary chondrocytes subjected to cyclic tensile strain.
• In vivo: Mouse anterior cruciate ligament transection (ACLT) model for OA, with interventions using adeno-associated virus (AAV) for Rcn2 manipulation and tamoxifen-induced gene deletion.
• Mechanism exploration: Investigated the interaction between Rcn2, Piezo1, and Stat3 signaling.

Main Results:

• Reticulocalbin-2 (Rcn2) was identified as a mechanosensitive factor upregulated in chondrocytes under mechanical overload.
• Rcn2 upregulation under mechanical loading is mediated by the Piezo1 channel.
• Chondrocyte-specific deletion of Rcn2 alleviated OA progression in ACLT mice, while Rcn2 overexpression accelerated it.
• Rcn2 promotes OA progression by enhancing Stat3 phosphorylation and nuclear translocation.

Conclusions:

• Rcn2 is a critical mediator of mechanical loading-induced OA.
• Targeting Rcn2, potentially through modulation of Piezo1 or Stat3 pathways, offers a therapeutic strategy for OA.
• This study reveals a novel molecular mechanism linking mechanical stress to OA pathogenesis via the Rcn2-Stat3 axis.