High glucose stimulating ECM remodeling and an inflammatory phenotype in the IPFP via upregulation of MFAP5 expression.

ABSTRACT

Extracellular matrix (ECM) remodeling and inflammation in the infrapatellar fat pad (IPFP) are associated with cartilage degeneration and the severity of osteoarthritis (OA). Diabetes is associated with the progression of OA. However, it is still unclear whether diabetes can promote osteoarthritis by targeting the IPFP. In this study, we established a high-fat diet/streptozotocin (HFD/STZ)-induced diabetes mouse model. We found that fibrosis and inflammation were more severe in the IPFP in diabetic mice. Transcriptomic profiling showed that MFAP5 expression was upregulated in IPFPs collected from diabetic mice compared to IPFPs collected from normal mice. We identified that Pdgfrα(+) progenitors were the primary source of MFAP5 in the IPFP under diabetic conditions. In addition, high glucose promoted the expression of MFAP5 in Pdgfrα(+) progenitors by stimulating the translocation of Yap1. Overexpression of MFAP5 in Pdgfrα(+) progenitors promoted fibrogenic differentiation and the production of IL-6. Knocking down the expression of MFAP5 efficiently prevented fibrosis and decreased the level of IL-6 in the IPFP and attenuated cartilage degeneration. Together, these results suggest that MFAP5 may be a potential novel therapeutic target for the treatment of diabetes-induced OA.