Excessive mechanical loading promotes osteoarthritis development by upregulating Rcn2

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-08, Vol.1870 (6), p.167251, Article 167251
• Main Authors: Liu, Yalin, Chen, Peng, Hu, Biao, Xiao, Ye, Su, Tian, Luo, Xianghang, Tu, Manli, Cai, Guangping
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Chondrocyte; Chondrocytes - metabolism; Chondrocytes - pathology; Disease Models, Animal; Ion Channels - genetics; Ion Channels - metabolism; Male; Mechanical overloading; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoarthritis; Osteoarthritis - genetics; Osteoarthritis - metabolism; Osteoarthritis - pathology; Rcn2; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stress, Mechanical; Up-Regulation; Weight-Bearing
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167251

Exposure of articular cartilage to excessive mechanical loading is closely related to the pathogenesis of osteoarthritis (OA). However, the exact molecular mechanism by which excessive mechanical loading drives OA remains unclear. In vitro, primary chondrocytes were exposed to cyclic tensile strain at 0.5 Hz and 10 % elongation for 30 min to simulate excessive mechanical loading in OA. In vivo experiments involved mice undergoing anterior cruciate ligament transection (ACLT) to model OA, followed by interventions on Rcn2 expression through adeno-associated virus (AAV) injection and tamoxifen-induced gene deletion. 10 μL AAV2/5 containing AAV-Rcn2 or AAV-shRcn2 was administered to the mice by articular injection at 1 week post ACLT surgery, and Col2a1-creERT: Rcn2flox/flox mice were injected with tamoxifen intraperitoneally to obtain Rcn2-conditional knockout mice. Finally, we explored the mechanism of Rcn2 affecting OA. Here, we identified reticulocalbin-2 (Rcn2) as a mechanosensitive factor in chondrocytes, which was significantly elevated in chondrocytes under mechanical overloading. PIEZO type mechanosensitive ion channel component 1 (Piezo1) is a critical mechanosensitive ion channel, which mediates the effect of mechanical loading on chondrocytes, and we found that increased Rcn2 could be suppressed through knocking down Piezo1 under excessive mechanical loading. Furthermore, chondrocyte-specific deletion of Rcn2 in adult mice alleviated OA progression in the mice receiving the surgery of ACLT. On the contrary, articular injection of Rcn2-expressing adeno-associated virus (AAV) accelerated the progression of ACLT-induced OA in mice. Mechanistically, Rcn2 accelerated the progression of OA through promoting the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (Stat3). •Rcn2 could act as a mechanosensitive factor in chondrocytes.•Rcn2 could mediate the effects of excessive mechanical loading on chondrocytes.•Rcn2 might act through promoting the phosphorylation and nuclear translocation of Stat3.