Blockage of Osteopontin-Integrin β3 Signaling in Infrapatellar Fat Pad Attenuates Osteoarthritis in Mice

The knowledge of osteoarthritis (OA) has nowadays been extended from a focalized cartilage disorder to a multifactorial disease. Although recent investigations have reported that infrapatellar fat pad (IPFP) can trigger inflammation in the knee joint, the mechanisms behind the role of IPFP on knee OA progression remain to be defined. Here, dysregulated osteopontin (OPN) and integrin beta 3 signaling are found in the OA specimens of both human and mice. It is further demonstrated that IPFP-derived OPN participates in OA progression, including activated matrix metallopeptidase 9 in chondrocyte hypertrophy and integrin beta 3 in IPFP fibrosis. Motivated by these findings, an injectable nanogel is fabricated to provide sustained release of siRNA Cd61 ((RGD-)Nanogel/siRNA Cd61) that targets integrins. The (RGD-)Nanogel possesses excellent biocompatibility and desired targeting abilities both in vitro and in vivo. Local injection of (RGD-) Nanogel/siRNA Cd61 robustly alleviates the cartilage degeneration, suppresses the advancement of tidemark, and reduces the subchondral trabecular bone mass in OA mice. Taken together, this study provides an avenue for developing (RGD-)Nanogel/siRNA Cd61 therapy to mitigate OA progression via blocking OPN-integrin beta 3 signaling in IPFP.

Automated summary

The study investigates the role of infrapatellar fat pad (IPFP) in knee osteoarthritis (OA) progression and identifies dysregulated osteopontin (OPN) and integrin beta 3 signaling in OA specimens. The study demonstrates that IPFP-derived OPN plays a role in OA progression, including chondrocyte hypertrophy and IPFP fibrosis. An injectable nanogel, (RGD-)Nanogel/siRNA Cd61, is developed to target integrins and effectively alleviate cartilage degeneration and subchondral bone mass in OA mice.