Association of Dipeptidylpeptidase 4 (CD26) With Chondrocyte Senescence and Radiographic Progression in Knee Osteoarthritis

Abstract

ObjectiveTo evaluate the association of dipeptidylpeptidase 4 (DPP‐4; also known as CD26) with cellular senescence of human cartilage and progression of knee osteoarthritis (OA).MethodsArticular cartilage sections and chondrocytes were acquired from 35 individuals undergoing total knee replacement for OA to evaluate the following: 1) the association between OA severity and established senescence markers (senescence‐associated β‐galactosidase activity and p16), which was quantified using immunohistochemistry and flow cytometry (n = 19 samples); 2) the coexpression of DPP‐4 with established senescence markers, which was assessed using flow cytometry; and 3) expression levels of anabolic and catabolic genes, senescence‐related genes, and senescence‐associated secretory phenotypes in DPP‐4+ and DPP‐4– cells, which were isolated using fluorescence‐activated cell sorting or magnetic‐activated cell sorting (n = 16 samples). The concentration of soluble DPP‐4 was measured in samples of synovial fluid and samples of plasma from the Prediction of Osteoarthritis Progression cohort and then evaluated for association with the severity of radiographic knee OA at baseline (n = 65 samples) and the progression of structural radiographic OA (n = 57 samples) over a 3‐year period.ResultsDPP‐4 expression was associated with higher senescence‐associated β‐galactosidase activity, p16 expression, senescence‐related gene and catabolic gene (ADAMTS5, MMP13, IL6, and IL8) expression, higher senescence‐associated secretory phenotype secretion, and lower anabolic gene (COL2A1 and ACAN) expression in primary chondrocytes. Synovial fluid DPP‐4 concentration was associated with radiographic OA progression (odds ratio 105.32; P = 0.015), proteases (synovial fluid matrix metalloproteinase 1 and matrix metalloproteinase 3), aggrecan degradation (synovial fluid sulfated glycosaminoglycan), indicators of activated macrophages (synovial fluid CD14 and CD163), and inflammation (synovial fluid interleukin‐6).ConclusionOur study identifies DPP‐4 as a key surface marker in senescent chondrocytes and a predictor of radiographic OA progression.image