Growth/Differentiation Factor 15 Promotes a Pro‐Regenerative Response in Chondrocytes Upon Cartilage Injury

Posttraumatic osteoarthritis (PTOA) is a special form of osteoarthritis (OA), developing after joint injuries. Except for some minor clinical differences, no biologic marker has yet been identified to distinguish idiopathic OA (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 and in a human ex vivo cartilage trauma model. GDF-15 levels were significantly higher in synovial fluid of PTOA patients as compared to IOA patients. We confirmed that fibroblast-like synoviocytes secreted GDF-15 after stimulation with medium of ex vivo-traumatized cartilage. Moreover, GDF-15 and its receptor, GFRAL, were 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. In fact, GDF-15 expression was mediated by oxidative stress and subsequent activation of p53. As a transcriptional target of p53, GDF-15 was associated with chondrosenescence. However, GDF-15 induced 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 senescence-associated but potentially pro-regenerative cytokine in the context of human PTOA.