TGFβ1-Induced Transglutaminase-2 Triggers Catabolic Response in Osteoarthritic Chondrocytes by Modulating MMP-13

Background: Transforming growth factor beta 1 (TGF beta 1) plays an essential role in maintaining cartilage homeostasis. TGF beta 1 is known to upregulate anabolic processes in articular cartilage, but the role of TGF beta 1 in chondrocyte catabolism remains unclear. Thus, we examined whether TGF beta 1 increases catabolic processes in the osteoarthritic joint via transglutaminase 2 (TG2). In this study, we investigated whether interplay between TGF beta 1 and TG2 mediates chondrocyte catabolism and cartilage degeneration in osteoarthritis. Methods: To investigate the role of TGF beta 1 and TG2 in osteoarthritis, we performed immunostaining to measure the levels of TGF beta 1 and TG2 in 6 human non-osteoarthritic and 16 osteoarthritic joints. We conducted quantitative reverse transcription polymerase chain reaction and western blot analysis to investigate the relationship between TGF beta 1 and TG2 in chondrocytes and determined whether TG2 regulates the expressions of matrix metalloproteinase (MMP)-13, type II, and type X collagen. We also examined the extent of cartilage degradation after performing anterior cruciate ligament transection (ACLT) and destabilization of the medial meniscus (DMM) surgery in TG2 knock-out mice. Results: We confirmed the overexpression of TGF beta 1 and TG2 in human osteoarthritic cartilage compared with non-osteoarthritic cartilage. TGF beta 1 treatment significantly increased the expression of TG2 via p38 and ERK activation. TGF beta 1-induced TG2 also elevated the level of MMP-13 and type X collagen via NF-kappa B activation in chondrocytes. Cartilage damage after ACLT and DMM surgery was less severe in TG2 knock-out mice compared with wild-type mice. Conclusion: TGF beta 1 modulated catabolic processes in chondrocytes in a TG2-dependent manner. TGF beta 1-induced TG2 might be the therapeutic target for treating cartilage degeneration and osteoarthritis.