Stimulation of α7-nAChRs coordinates autophagy and apoptosis signaling in experimental knee osteoarthritis

Osteoarthritis (OA) is the most common chronic joint disease in the elderly population. Growing evidence indicates that a balance between autophagy and apoptosis in chondrocytes plays a key role in OA's cartilage degradation. Thus, drugs targeting the balance between apoptosis and autophagy are potential therapeutic approaches for OA treatment. In previous studies, we found that the activation of alpha 7 nicotinic acetylcholine receptors (alpha 7-nAChRs) alleviated monosodium iodoacetate (MIA)-induced joint degradation and osteoarthritis pain. To explore the potential functions of alpha 7-nAChRs in autophagy and apoptosis signaling in knee OA, we compared the expression of alpha 7-nAChRs in human knee articular cartilage tissues from normal humans and OA patients. We found that knee joint cartilage tissues of OA patients showed decreased alpha 7-nAChRs and an imbalance between autophagy and apoptosis. Next, we observed that alpha 7-nAChRs deficiency did not affect cartilage degradation in OA development but reversed the beneficial effects of nicotine on mechanical allodynia, cartilage degradation, and an MIA-induced switch from autophagy to apoptosis. Unlike in vivo studies, we found that primary chondrocytes from alpha 7-nAChRs knockout (KO) mice showed decreased LC3 levels under normal conditions and were more sensitive toward MIA-induced apoptosis. Finally, we found that alpha 7-nAChRs deficiency increased the phosphorylation of mTOR after MIA treatment, which can also be observed in OA patients' tissues. Thus, our findings not only confirmed that nicotine alleviated MIA-induced pain behavior and cartilage degradation via stimulating the alpha 7-nAChRs/mTOR signal pathway but found the potential role of alpha 7-nAChRs in mediating the balance between apoptosis and autophagy.