Abstract
MicroRNAs (miRNAs) contribute to osteoarthritis (OA) development. Nevertheless, the function and mechanism of miR-30b-5p in OA are unclear. In the present article, we gauged the miR-30b-5p level in OA patients and analyzed its correlation with OA stages. Then, we conducted in-vivo and in-vitro gain-of-function assays to determine the function of miR-30b-5p, silent information regulator 2 homolog 1 (SIRT1) and Fox. Cell counting Kit-8 (CCK-8) assay, BrdU assay and flow cytometry were utilized to gauge cell viability and apoptosis of human chondrocyte (HC-A). The targeting association between miR-30b-5p and SIRT1 was validated through the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment. The results signified that miR-30b-5p was up-regulated in OA patients, OA rats and interleukin-1β (IL-1β)-induced chondrocytes. The higher miR-30b-5p expression brought about progressive stages of OA patients and enhanced levels of pro-inflammatory mediators in the synovial fluid. Functionally, overexpressing miR-30b-5p hampered cell viability, aggravated chondrocyte apoptosis and NLRP3 inflammasome activation induced by IL-1β, while down-regulating miR-30b-5p exerted the reverse effects. The in-vivo experiment exhibited that down-regulating miR-30b-5p improved joint pain and loss of articular cartilage in the rats with restrained inflammation and NLRP3 inflammasome activation. Mechanistically, miR-30b-5p targeted the 3’-non-translated region (3’UTR) of SIRT1, and miR-30b-5p was inducible with NF-κB phosphorylation enhancement. Overexpressing SIRT1 or inhibiting NF-κB relieved miR-30b-5p-induced apoptosis and NLRP3 inflammasome activation by promoting FoxO3a, while down-regulating SIRT1 or FoxO3a reversed miR-30b-5p-in-induced anti-inflammatory and apoptosis-suppressive effects. Collectively, NF-κB-induced miR-30b-5p modulates chondrocyte apoptosis and OA progression by regulating the SIRT1-FoxO3a-mediated NLRP3 inflammasome.
Highlights
Osteoarthritis (OA) is a chronic arthropathy associated with articular degeneration, manifested as articular cartilage degeneration and bone hyperplasia, often found in the elderly [1, 2]
A large number of studies have proved that cytokines and growth factors produced by articular cartilage under the action of mechanical and physical and chemical factors such as trauma, inflammation and infection contribute to OA pathogenesis
Some studies have shown that miR-30 family members miR30b, miR-30c, miR-30d and miR-30e are reversely related to Runx2 expression under mechanical unloading conditions, which impede osteoblast differentiation by repressing Runx2 in MC3T3-E1 cells [28]
Summary
Osteoarthritis (OA) is a chronic arthropathy associated with articular degeneration, manifested as articular cartilage degeneration and bone hyperplasia, often found in the elderly [1, 2]. OA is usually manifested as joint pain and poor movement, and subchondral ossification, trabecular fracture, and cystic changes are shown under X-ray examination [3]. The OA incidence rate is on the rise due to population aging. Studies have stated that multiple inflammatory factors, such as TNF-α, IL-6 and IL-1β, contribute to OA development. The elevation of IL-1β facilitates the profiles of cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS), expediting OA development [4]. It is crucial to inquiry into the www.aging-us.com specific mechanism of OA and reduce the inflammatory mediator release in OA treatment
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