ANR ArNAC : Benjamin Lauzier (2025-2029)

Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are two chronic, degenerative conditions with significant socioeconomic burdens that currently lack effective treatments. OA and IVDD share similar disease-associated degenerative processes, as evidenced by overlapping tissue alterations (including tissue damage, extracellular matrix degradation, and disrupted bone homeostasis) and deregulated molecular pathways (inflammation, autophagy, oxidative stress, apoptosis, and cellular senescence). The Wnt/β-catenin pathway is one of the key signaling pathways deregulated in both diseases. Indeed, aberrant activation of this pathway has been shown to contribute to the progression of both IVDD and OA. Recently, O-GlcNAcylation, a reversible post-translational modification of proteins that regulate cellular functions has been demonstrated to occur on β-catenin. This leads to β-catenin stabilization and an increased interaction with the methyltransferase EZH2. Notably, EZH2 activity is also implicated in the catabolic processes associated with OA and IVDD. Furthermore, elevated O-GlcNAc levels have been observed in degenerated tissues from OA and IVDD patients. We hypothesize that the O-GlcNAcylation of proteins, particularly β-catenin, plays a role in the pathological processes of OA and IVDD. The ArNAc project proposes to i) Investigate the O-GlcNAcylation status of β-catenin and its molecular effects in OA and IVDD cells; ii) Identify other O-GlcNAcylated proteins in OA and IVDD in human and rat models; iii) Develop therapeutic tools targeting specific protein O-GlcNAcylation such as β-catenin; and iv) Assess the therapeutic potential of modulating β-catenin O-GlcNAcylation in OA and IVDD animal models. Ultimately, the ArNAc project aims to significantly enhance our understanding of the pathophysiology of OA and IVDD, while exploring new therapeutic strategies that could modulate O-GlcNAcylation in key proteins, including β-catenin.