The Role of the Non-neuronal Cholinergic System in Inflammation and Degradation Processes in Osteoarthritis

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 alpha 7-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 alpha 7-nACh subunit, called CHRFAM7A, which is responsible for truncated alpha 7-nAChR. We assessed the effect of nAChR on chondrocytes activated by interleukin-1 beta (IL-1 beta) and the involvement of alpha 7-nAChR using chondrocytes from wild-type (WT) and alpha 7-deficient Chrna7(-/-) mice. The role of alpha 7-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 alpha 7-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-1 beta-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 alpha 7-nAChR, but the anticatabolic activity may be mitigated by truncated alpha 7-nAChR in human chondrocytes. In vivo experiments strongly suggest that alpha 7-nAChR has a protective role in OA.