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The Role of the Non-neuronal Cholinergic System in Inflammation and Degradation Processes in Osteoarthritis (Team Berenbaum)

July 09 - 2020

Alice Courties, Ariane Do, Sarah Leite, Manon Legris, Laure Sudre, Audrey Pigenet, Juliette Petit, Geoffroy Nourissat, Adeline Cambon-Binder, Uwe Maskos, Francis Berenbaum, Jeremie Sellam

Arthritis Rheumatol. 2020

OBJECTIVE: 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 undertook this study to investigate 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 alpha7-nAChR, in human OA and murine chondrocytes was determined by polymerase chain reaction and ligand-binding. We investigated the messenger RNA expression of the human duplicate alpha7-nACh subunit, called CHRFAM7A, which is responsible for truncated alpha7-nAChR. We assessed the effect of nAChR on chondrocytes activated by interleukin-1beta (IL-1beta) and the involvement of alpha7-nAChR using chondrocytes from wild-type (WT) and alpha7-deficient Chrna7(-/-) mice. The role of alpha7-nAChR in OA was explored after medial meniscectomy in WT and Chrna7(-/-) mice.

RESULTS: Human and murine chondrocytes express the biochemical partners of the non-neuronal cholinergic system and a functional alpha7-nAChR at their cell surface (n = 5 experiments with 5 samples each). The expression of CHRFAM7A in human OA chondrocytes (n = 23 samples) correlated positively with matrix metalloproteinase 3 (MMP-3) (r = 0.38, P < 0.05) and MMP-13 (r = 0.48, P < 0.05) expression. Nicotine decreased the IL-1beta-induced IL-6 and MMP expression, in a dose-dependent manner, in WT chondrocytes but not in Chrna7(-/-) chondrocytes. Chrna7(-/-) mice that underwent meniscectomy (n = 7) displayed more severe OA cartilage damage (mean +/- SD Osteoarthritis Research Society International [OARSI] score 4.46 +/- 1.09) compared to WT mice that underwent meniscectomy (n = 9) (mean +/- SD OARSI score 3.05 +/- 0.9; P < 0.05).

CONCLUSION: The non-neuronal cholinergic system is functionally expressed in chondrocytes. Stimulation of nAChR induces antiinflammatory and anticatabolic activity through alpha7-nAChR, but the anticatabolic activity may be mitigated by truncated alpha7-nAChR in human chondrocytes. In vivo experiments strongly suggest that alpha7-nAChR has a protective role in OA.

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