OLYMPiC2024

Osteoarthritis (OA) is a painful joint disease affecting over 500 million people worldwide with a considerable socio-economic burden. OA is characterized by the degradation of the articular cartilage, various degrees of synovial tissue inflammation (synovitis) and the formation of osteophytes altogether leading to the loss of joint function. Facing the absence of therapeutic options that can halt or reverse this debilitating condition, and considering the major public health concern represented by OA, the World Health Organization (WHO) has included OA in its top priority diseases. Research on OA perfectly matches the United Nations decade of healthy ageing (2021-30) and there are pressing needs for the identification of novel strategies to improve disease monitoring and to support the development of novel therapeutic approaches. It is now acknowledged that OA is a very heterogeneous disease with multiple clinical phenotypes and that synovial tissue may present significant changes early in the disease development, even before cartilage and bone alterations. Three distinct synovial pathotypes were identified in the context of OA by our international consortium and preliminary evidence pointed for a relevant relationship between these pathotypes and the clinical features of the patients. We believe that a better understanding of these various histopathological features will help accurately stratify OA patients, and design efficient treatments for OA with a personalised approach. Moreover, the involvement of the innate immune response and the complex interplay between synovial innate cells and their environment is increasingly recognized as key drivers of the development and perpetuation of OA. Innate lymphoid cells (ILC) are innate lymphocytes having an important role in maintaining tissue homeostasis. Preliminary data from our international consortium highlighted that distinct ILC subsets can be found in the synovium of both OA patients and a relevant mouse model of OA. ILC accumulation correlated with synovial inflammation, suggesting a role for ILC in regulating synovial immune cell responses. Recent studies reported a role for the microbiota in shaping activation of ILC and showed that modification in the microbiota led to joint pathophysiology and promoted the development of OA, suggesting a potential correlation between ILC/microbiota and OA. Through the ANR PRCI “OLYMPiCS2024” project, and based on strong preliminary data and solid literature evidence, our Franco-German consortium aims at: - Deciphering the diversity and spatial distribution of ILC in joint tissues at different stages of OA and the correlation with the clinical features of the patients. - Investigating the contribution of ILC subsets to the pathophysiology of OA and evaluating therapeutic agents aimed at modulating ILC activation in OA models. - Studying the role of the microbiota-dependent regulation of ILC in relevant models of OA, to bring the proof of concept for a diet-based microbiota/ILC-modulating strategy in OA dog patients. This project involves the complementary and multidisciplinary expertise of French and German research teams in OA pathophysiology, synovial histopathology and ILC biology in homeostasis and diseases, as well as our experience in evaluating therapeutic approaches aimed at both modulating inflammation and ILC activation in several preclinical models. Overall, OLYMPiC2024 has all the ingredients for advancing scientific and translational research in OA and an important potential for proposing therapeutic strategies with a concrete impact on OA patients’ quality of life in the near future.