Chen_2023_Arthritis.Rheumatol__

OBJECTIVE: To evaluate the association of Dipeptidyl-peptidase 4 (DPP4, also known as CD26) with cellular senescence of human cartilage and knee osteoarthritis (OA) progression. METHODS: Articular cartilage sections and chondrocytes were acquired from 35 individuals undergoing total knee replacement for OA to evaluate: (1) the association between OA severity and established senescence markers (SA-beta-gal activity and p16) quantified by immunohistochemistry and flow cytometry (n=19); (2) the co-expression of DPP4 with established senescence markers by flow cytometry, and (3) expression levels of anabolic and catabolic genes, senescence related genes and senescence-associated secretory phenotypes (SASPs) in DPP4(+) and DPP4(-) cells, isolated by fluorescence-activated cell sorting vs magnetic-activated cell sorting (n=16). The concentration of soluble DPP4 was measured in synovial fluid (SF) and plasma of the Prediction of Osteoarthritis Progression cohort, and evaluated for its association with knee radiographic OA (rOA) severity at baseline (n=65) and structural rOA progression (n=57) over three years. RESULTS: DPP4 expression was associated with higher SA-beta-gal, p16 expression, senescence-related gene and catabolic gene (ADAMTS5, MMP13, IL6, and IL8) expression, higher SASPs secretion, and lower anabolic gene (COL2A1 and ACAN) expression in primary chondrocytes. SF DPP4 was associated with rOA progression (Odds ratio=105.32, p=0.015), proteases (SF MMP-1 and -3), aggrecan degradation (SF sGAG), indicators of activated macrophages (SF CD14 and CD163) and inflammation (SF IL-6). CONCLUSION: Our study identifies DPP4 as a key surface marker of senescent chondrocytes, and a predictor of rOA progression.