Linear ubiquitination of LKB1 activates AMPK pathway to inhibit NLRP3 inflammasome response and reduce chondrocyte pyroptosis in osteoarthritis

作者：Yang Chen, Yiheng Liu, Kai Jiang, Zi Wen, Xu Cao, Song Wu · 发表于：Journal of Orthopaedic Translation · 年份：2022 · DOI：10.1016/j.jot.2022.11.002 · 被引用次数：65 · 研究领域：Inflammasome and immune disorders、Osteoarthritis Treatment and Mechanisms、Bone Metabolism and Diseases

Background: Osteoarthritis (OA) is the most common chronic disease. It is characterized by high levels of clinical heterogeneity and low inflammation. Therefore, elucidation of the mechanisms that regulate gene expression is critical for developing effective OA therapies. This study aimed to explore the role of LKB1/AMPK in the progression of OA. Methods: Anterior cruciate ligament transection (ACLT) was performed on Sprague Dawley (SD) rats right knee to construct OA model, followed by AICAR [AMP-activated protein kinase (AMPK) activator] treatment. The level changes [AMPK, IL-10, IL-13, IL-1β, TNF-α, IL-6, ASC, Caspase-1, Ki67, and hibit Nod-like receptor protein 3 (NLRP3)] and the degree of tissue injury were assessed by western blot, Immunohistochemical (IHC), Enzyme-linked immunosorbent assay (ELISA), Hematoxylin-eosin staining (HE), Immunofluorescence (IF), Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and Safranin O and Fast Green staining (S-O). Human chondrocytes were induced by LPS to construct a cellular inflammatory model, and then transfected with oe-AMPK or oe-HOIL-1-interacting protein (HOIP). Cell viability/apoptotic and intracellular content of AMPK, HOIP, IL-1β, IL-10, IL-13, TNF-α, IL-6, ASC, NLRP3 and Caspase-1 were measured by western blot, ELISA, CCK-8, IF, flow cytometry and TUNEL assays. Results: After AICAR treatment with OA rats, the expression of p-AMPK, IL-10, IL-13, Ki67 and Bcl-2 increased, the level of NLRP3 inflamm...