The role of the non‐neuronal cholinergic system in inflammation and degradation processes in osteoarthritis

Alice Courties (1, 2) , Ariane Do (1, 2) , Sarah Leite (1, 2) , Manon Legris (1, 2) , Laure Sudre (1, 2) , Audrey Pigenet (1, 2) , Juliette Petit (1, 2) , Geoffroy Nourissat (1, 3) , Adeline Cambon-Binder (1) , Uwe Maskos (4) , Francis Berenbaum (1, 2) , Jérémie Sellam (1, 2)

1 Pathologies biliaires, fibrose et cancer du foie [CRSA]
2 CHU Saint-Antoine [AP-HP]
3 Clinique Maussins Nollet - Ramsay (FRANCE)
4 NISC - Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems

Objectives The non‐neuronal cholinergic system represents non‐neuronal cells that have the biochemical machinery to synthetize de novo and/or respond to acetylcholine (ACh). We investigated this biochemical machinery in chondrocytes and its involvement in osteoarthritis (OA). Methods Expression of the biochemical machinery for ACh metabolism and nicotinic ACh receptors (nAChR), particularly α7nAChR, in human OA and murine chondrocytes was determined by PCR and ligand‐binding. We investigated the mRNA expression of the human duplicate α7nACh subunit, called CHRFAM7A, which is responsible for a truncated α7nAChR. We assessed the effect of nAChR on chondrocytes activated by IL1β and the involvement of α7nAChR using chondrocytes from wild‐type (WT) and α7‐deficient Chrna7‐/‐mice. The role of α7nAChR in OA was explored after medial meniscectomy (MNX) in WT and Chrna7‐/‐mice. Results Human and murine chondrocytes express the biochemical partners of the non‐neuronal cholinergic system (n=5) and a functional α7nAChR at their cell surface. The expression of CHRFAM7A in human OA chondrocytes correlated positively with MMP3 (r=0.38, p<0.05) and MMP13 (r=0.48, p<0.05) expression (n=23). Nicotine decreased the IL1β‐induced IL6 and MMPs expression in a dose‐dependent manner in WT but not in Chrna7‐/‐chondrocytes. MNX Chrna7‐/‐mice displayed more severe OA cartilage damage (OARSI score of 4.46±1.09, n=7) than MNX WT mice (3.05±0.9, n=9, p<0.05). Conclusion The non‐neuronal cholinergic system is functionally expressed in chondrocytes. Stimulation of nAChR induces anti‐inflammatory and anti‐catabolic activity through α7nAChR, but the anti‐catabolic activity may be mitigated by truncated α7nAChR in human chondrocytes. In vivo experiments strongly suggest that α7nAChR has a protective role in OA.

Domaines: Sciences cognitives

Alice Courties, Ariane Do, Sarah Leite, Manon Legris, Laure Sudre, et al.. The role of the non‐neuronal cholinergic system in inflammation and degradation processes in osteoarthritis. Arthritis & rheumatology, 2020, ⟨10.1002/art.41429⟩. ⟨pasteur-02935940⟩