p53-induced GDF-15 expression promotes a pro-regenerative response in human chondrocytes upon cartilage injury

Posttraumatic osteoarthritis (PTOA) is a special form of OA, developing after joint injuries. Except for some minor differences between the clinical characteristics of patients suffering from idiopathic OA (IOA) and PTOA, no biologic marker has yet been identified to distinguish IOA from PTOA. In this study, we investigated the expression of the stress-responsive cytokine growth differentiation factor 15 (GDF-15) in clinical samples from the Ulm OA study cohort (PTOA: n =12; IOA: n=54) and in a human ex vivo cartilage trauma model. We found significantly higher GDF-15 levels in synovial fluid of end-stage PTOA patients as compared to IOA patients. Further, we confirmed that fibroblast-like synoviocytes secreted increased levels of GDF-15 after stimulation with medium of ex vivo-traumatized cartilage. GDF-15 and its receptor, GFRAL, were significantly elevated in highly degenerated OA cartilage. By means of a human cartilage trauma model, we discovered that chondrocytes produced GDF-15 upon tissue injury, while antioxidative treatment attenuated GDF-15 secretion. We confirmed that oxidative stress and subsequent activation of p53 resulted in GDF-15 expression. As a transcriptional target of p53, GDF-15 was associated with chondrosenescence. Although the cytokine might therefore represent a senescence-associated secretory phenotype (SASP) factor, stimulation with exogenous GDF-15 did not cause detrimental effects but induced a pro-regenerative response in chondrocytes, characterized by enhanced proliferation as well as chondro- and cell protection after cartilage trauma. Overall, this study first describes GDF-15 as a stress-responsive and potentially pro-regenerative cytokine in the context of human PTOA.