Sorbonne Université, INSERM UMR 938, Centre de Recherche Saint-Antoine, Hôpital Saint-Antoine, AP-HP, Paris, France.
2INSERM UMR 938, Centre de Recherche Saint-Antoine, Clinique Maussins, Groupe Ramsay Générale de Santé, Paris, France.
Arthritis Rheumatol. 2020 Dec;72(12):2072-2082. doi: 10.1002/art.41429. Epub 2020 Oct 25.
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).
Expression of the biochemical machinery for ACh metabolism and nicotinic ACh receptors (nAChR), particularly α7-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 α7-nACh subunit, called CHRFAM7A, which is responsible for truncated α7-nAChR. We assessed the effect of nAChR on chondrocytes activated by interleukin-1β (IL-1β) and the involvement of α7-nAChR using chondrocytes from wild-type (WT) and α7-deficient Chrna7 mice. The role of α7-nAChR in OA was explored after medial meniscectomy in WT and Chrna7 mice.
Human and murine chondrocytes express the biochemical partners of the non-neuronal cholinergic system and a functional α7-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-1β-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).
The non-neuronal cholinergic system is functionally expressed in chondrocytes. Stimulation of nAChR induces antiinflammatory and anticatabolic activity through α7-nAChR, but the anticatabolic activity may be mitigated by truncated α7-nAChR in human chondrocytes. In vivo experiments strongly suggest that α7-nAChR has a protective role in OA.
非神经元胆碱能系统代表具有从头合成和/或对乙酰胆碱（ACh）作出反应的生化机制的非神经元细胞。我们进行这项研究是为了调查软骨细胞中的这种生化机制及其在骨关节炎（OA）中的作用。
通过聚合酶链反应和配体结合，确定人 OA 和鼠软骨细胞中 ACh 代谢和烟碱型乙酰胆碱受体（nAChR）的生化机制表达，特别是α7-nAChR。我们研究了负责截断α7-nAChR 的人重复α7-nACh 亚基，即 CHRFAM7A 的信使 RNA 表达。我们评估了 nAChR 对白细胞介素 1β（IL-1β）激活的软骨细胞的影响，并使用野生型（WT）和α7 缺陷型 Chrna7 小鼠的软骨细胞研究了α7-nAChR 的作用。在 WT 和 Chrna7 小鼠进行内侧半月板切除术之后，我们探讨了α7-nAChR 在 OA 中的作用。
人软骨细胞和鼠软骨细胞在其细胞表面表达非神经元胆碱能系统的生化伴侣和功能性α7-nAChR（n = 5 个实验，每个实验 5 个样本）。人 OA 软骨细胞中 CHRFAM7A 的表达（n = 23 个样本）与基质金属蛋白酶 3（MMP-3）（r = 0.38，P < 0.05）和 MMP-13（r = 0.48，P < 0.05）的表达呈正相关。尼古丁以剂量依赖性方式降低 WT 软骨细胞中 IL-1β 诱导的 IL-6 和 MMP 表达，但在 Chrna7 软骨细胞中则没有。与接受半月板切除术的 WT 小鼠（n = 9）相比，接受半月板切除术的 Chrna7 小鼠（n = 7）的 OA 软骨损伤更严重（平均 ± SD 骨关节炎研究协会国际评分 4.46 ± 1.09）（平均 ± SD OARSI 评分 3.05 ± 0.9；P < 0.05）。
非神经元胆碱能系统在软骨细胞中具有功能性表达。nAChR 的刺激通过α7-nAChR 诱导抗炎和抗分解代谢活性，但在人软骨细胞中，截断的α7-nAChR 可能会减轻抗分解代谢活性。体内实验强烈表明，α7-nAChR 在 OA 中具有保护作用。
