Abstract
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation. Alpha 7 nicotinic acetylcholine receptor (α7nAChR) is associated with inflammatory and metabolic responses in OA. However, the mechanisms underlying the pathological process of OA remain unclear. The aim of the present study was to examine the role and mechanisms of α7nAChR-mediated autophagy and anti-inflammatory response in chondroprotection. Monosodium iodoacetate (MIA)-induced Wistar rat OA model was used to assess the in vivo effects of the ɑ7nAChR agonist (PNU-282987). The histopathological characteristics of OA were evaluated by immunohistochemistry (IHC), and the levels of autophagy markers were determined by western blotting and transmission electron microscopy. The anti-inflammatory effect of the ɑ7nAChR agonist was assessed by IHC, quantitative real-time polymerase chain reaction, and western blotting. Parallel experiments to determine the molecular mechanisms through which the ɑ7nAChR agonist prevents OA were performed using interleukin-1β (IL-1β)-treated chondrocytes. Our results showed that PNU-282987 reduced cartilage degeneration and matrix metalloproteinase (MMP)-1 and MMP-13 expressions. Activating α7nAChR with PNU-282987 significantly promoted MIA/IL-1β-induced chondrocyte autophagy, as demonstrated by the increase in LC3-II/LC3-I ratio, Beclin-1 levels, and autophagosome number. Furthermore, treating chondrocyte with ULK1 siRNA attenuated the PNU282987-induced enhancement of LC3-II/LC3-I ratio and Beclin-1 level. Additionally, PNU282987 suppressed NF-κB/NLRP3 inflammasome activation by inhibiting the ROS/TXNIP pathway and suppressed tumor necrosis factor-ɑ and IL-1β secretion in MIA/IL-1β-treated chondrocytes. Our results demonstrate that the activation of α7nAChR promotes chondrocyte autophagy and attenuates inflammation to mitigate OA progression, providing a novel target for the treatment of OA.
Highlights
Osteoarthritis (OA) is a highly prevalent disease and a leading cause of disability and chronic pain [1, 2]
The results revealed that the protein levels of matrix metalloproteinase (MMP)-1 and MMP-13 were suppressed, while the protein level of collagen II was increased after PNU-282987 treatment in vivo (Fig 1C)
These results demonstrate that the activation of a7nAChR can reduce articular cartilage damage and promote protective autophagy in rats with OA
Summary
Osteoarthritis (OA) is a highly prevalent disease and a leading cause of disability and chronic pain [1, 2]. The personal and social burden of OA is increasing, and the current treatment options lack disease mitigation abilities and are limited to pain relief to maintain joint function. The only definitive treatment option is surgical joint replacement. Safe and effective therapeutic drugs for the early treatment of OA must be explored. The α7 (α7nAChR) subtype is important for immune regulation [3]. Researchers have previously demonstrated that the activation of α7nAChR can help reduce a variety of inflammatory and immune-related diseases by triggering the cholinergic anti-inflammatory pathway [4, 5]. Recent evidence indicates that α7nAChR has a relieving effect on OA [6]. The underlying mechanisms by which α7nAChR functions have not been fully elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
