Knee Fibrosis Is Associated With The Development Of Osteoarthritis In A Murine Model Of Tibial Compression

Fibrosis in the synovium and infrapatellar fat pad (IFP) is frequently observed in knee osteoarthritis (OA) and is often correlated with joint pain and stiffness. However, the mechanisms underpinning the development of knee fibrosis in OA are relatively poorly understood. In this study, we used a combination of histological, immunohistochemical, and multiplex gene expression analyses to characterize the fibrosis that develops in a mouse model of load-induced OA. Histological evaluation showed the time-dependent development of fibrosis in the synovium, capsule, and IFP of loaded limbs of male 11-week-old mice. The development of load-induced fibrosis was accompanied primarily by proliferation, expansion, and activation of the stromal compartment, and by increased macrophage presence evidenced by increased F4/80 and MAC2 positive immunostaining. The presence of B and T-cells was minimal in both control and loaded limbs, but CD3-positive immunostaining was significantly higher in C57BL/6J at 2 weeks after loading, indicating an increased presence of T-cells. Using NanoString gene expression analyses of human and mouse tissues, we found that mice subjected to cyclic loading recapitulated the gene expression profile observed in human fibrotic tissues, including increased expression of collagen genes. Together, our results indicate that this well-controlled nonsurgical mouse model can be used to study the mechanisms underpinning the development of knee fibrosis, and potentially to test targeted strategies to prevent the development of fibrosis and stiffness of the knee.