PPAROA

Osteoarthritis (OA) is the most common inflammatory, degenerative and painful joint disorder. Despite the increase in the incidence of OA, there is still no effective treatment capable of restoring the structure of articular cartilage and function of damaged joints. Consequently, mesenchymal stromal/stem cell (MSC)-based therapies have become a thriving area of research. Pre-clinical and phase I or II clinical studies have shown that intra-articular MSC injection is well-tolerated. In this context, partner 1 (INSERM U1229-RMES/Nantes) coordinates, since 2013, a clinical trial “Arthrostem” (NCT: 01879046) that aims at assessing the immunomodulatory and anti-osteoarthritic properties of bone marrow-MSC (BM-MSC) and adipose tissue-MSC (AT-MSC) harvested from the same osteoarthritic patient. Currently, thanks to this clinical trial, a biocollection of MSC from 30 OA patients has been constituted. For its part, Partner 2 (INSERM U1183-IRMB/Montpellier), within an ongoing H2020 program, coordinates ADIPOA2 a randomized controlled study to validate the efficacy of the intra-articular injection of AT-MSC in mild to moderate knee OA. Moreover, partner 2 has demonstrated the capacity of human MSC, to reduce the clinical severity of OA by decreasing inflammation and protecting chondrocytes from apoptosis and loss of phenotype. However and despite their clinical efficacy in human OA, MSC display poor in vivo survival and engraftment rate. This in vivo ephemeral presence of MSC after injection has raised the possibility that their therapeutic effects in OA were mediated through the release of chondro-protective molecules and/or the education of immune cells towards a regulatory phenotype. In line with this hypothesis, partner 2 has shown that besides their capacity to protect chondrocytes, MSC control the fate of macrophages by switching their phenotype from pro-inflammatory M1 to anti-inflammatory M2. In OA patients and as described above, although MSC are considered safe when intra-articularly administrated, their therapeutic effects remain to be further improved to warrant long-term benefits and turn them into a routine OA treatment in clinical practice. Interestingly, data have suggested a role for PPARß/d in the onset and severity of murine OA and partner 2 has recently demonstrated that PPARß/d expression level predicts MSC immunomodulatory potential and more importantly that its inhibition stimulates their therapeutic effects in murine arthritis. Considering the safety and promising therapeutic effect of MSC in OA as well as the potential role of PPARß/d in the immunomodulatory properties of MSC, the overall objective of the PPAROA project is to investigate whether a modulation of PPARß/d can improve the MSC therapeutic properties in OA. Particular attention will be paid to (i) deciphering the role of PPARß/d in the therapeutic effects of BM-MSC and AT-MSC collected from Arthrostem OA patients and (ii) investigating whether PPARß/d modulation in MSC may enhance and prolong their anti-OA therapeutic effect. To address these issues, PPAROA will be organized in 3 scientific work packages (WP): •WP1: Role of PPARß/d in the immunomodulatory properties of BM-MSC and AT-MSC on cells of innate and adaptive immune system •WP2:Role of PPARß/d in the chondro-protective properties of BM-MSC and AT-MSC •WP3: Role of PPARß/d on the therapeutic effects of BM-MSC and AT-MSC in OA preclinical models. In case of success, this 4-year ambitious project will undoubtedly lead us to consider clinical trials and thus pave the way of new therapeutic avenue in the management of OA patients.