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

Abstract

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 𝜷3 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 𝜷3 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 𝜷3 signaling in IPFP.

Immunoregulatory Roles of Osteopontin in Diseases

“…Dai et al found that OPN and integrin β3 were upregulated in the infrapatellar fat pad (IPFP) and calcified cartilage in OA mice as well as in humans and that IPFP-derived OPN contributed to cartilage degeneration, subchondral bone remodeling and IPFP fibrosis via OPN–integrin β3 signaling. Their study also showed that intra-IPFP injection of RGD-nanogel/siRNA Cd61, which specifically targeted the IPFP cells expressing OPN receptors, effectively reduced the expression of integrin β3 and attenuated OA progression in mice [ 107 ]. Luo, W. et al also reported that OPN, CD44 and HA synthase 1 (HAS1) were highly expressed in OA cartilage and chondrocytes, and OPN upregulated the expression of HAS1 and increased the anabolism of the synthesis of ECM components such as hyaluronic acid (HA) in cartilage through CD44 protein expression in OA mice, thereby inhibiting OA progression.…”

The role of targeting glucose metabolism in chondrocytes in the pathogenesis and therapeutic mechanisms of osteoarthritis: a narrative review

“…When chondrocytes are subjected to abnormal mechanical stimulation, such as overloading or joint injury, their metabolic balance is altered, leading to matrix loss and tissue degeneration, which can lead to osteoarthritis (OA) ( 4 , 5 ). OA is one of the most common and diverse degenerative diseases with complex pathogenesis that affects all joint tissues, characterized by cartilage degeneration, osteophyte formation, meniscal degeneration, subchondral bone remodeling, joint inflammation and fibrosis of the infrapatellar fat pad ( 6 – 12 ). The main clinical manifestations of OA patients are AC degeneration, subchondral bone sclerosis, synovitis, osteophyte formation, joint pain and disability ( 13 ).…”