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

## TL;DR

This study shows that GDF-15, a stress-related protein, increases after cartilage injury and may help protect and regenerate cartilage in posttraumatic osteoarthritis.

## Contribution

The study first identifies GDF-15 as a senescence-associated yet pro-regenerative cytokine in human posttraumatic osteoarthritis.

## Key findings

- GDF-15 levels are significantly higher in synovial fluid of PTOA patients compared to IOA patients.
- GDF-15 is produced by chondrocytes after cartilage injury and is mediated by oxidative stress and p53 activation.
- GDF-15 promotes chondrocyte proliferation and cell protection after cartilage trauma.

## Abstract

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.

After cartilage injury, oxidative stress results in a posttraumatic cell fate decision: Intracellular ROS accumulation initiates a p53‐dependent stress response in chondrocytes, including the transcription of signature genes, such as CDKN1A and GDF15. Ongoing oxidative stress leads to stress‐induced premature senescence of chondrocytes and excessive secretion of GDF‐15. GDF‐15 binding to GFRAL promotes proliferation, migration, and survival of adjacent chondrocytes.