Dopamine Delays Articular Cartilage Degradation In Osteoarthritis By Negative Regulation Of The NF-?B And JAK2/STAT3 Signaling Pathways

Background Osteoarthritis is a common chronic degenerative disease characterized by degradation of the cartilage?synovitis?subchondral osteosclerosis?hypertrophy of the joint capsule.Under the background of aging population,the incidence of OA has increased significantly,and seriously affecting the patients daily life,as well as imposing a heaving economic burden on family and society.OA has been viewed as a degenerative joint disease caused by normal wear and tear on the body,but increasingly studies have demonstrated that inflammation plays an important part in its pathogenesis.Excessive delivery of proinflammation cytokines,such as IL-1?(interleukin-1?),IL-6(interleukin-6)and TNF-?(tumor necrosis factor-?)were detected within areas of cartilage in OA patients,elevated serum levels of CRP(C-reactionprotein)are predictive of the development and progression of OA.These cytokines can lead to the upregulated expression of MMP-1(matrix metalloproteinase-1),MMP-3,MMP-13 and other catabolic enzymes to degrade the extracellular matrix.Dopamine(DA)is a neurotransmitter in the central nervous system that controls motor,emotional,cognitive,and neuroendocrine functions.Previous studies have shown that DA inhibits IL-6,TNF-a and i NOS(inducible nitric oxide synthase)overproduction by suppressing the activation of the NF-?B signaling pathway,indicating its underlying anti-inflammatory mechanisms.Therefore,it is deserved to investigate the application of DA for OA treatment.Objective To investigate whether DA can delay the progression of OA and its mechanism.Methods 1.Human primary chondrocytes were isolated and culture,the cytotoxicity of DA for chondrocytes was detected by CCK-8(cell counting kit 8)assay.2.Pro-inflammatory cytokine IL-1? was applied to stimulate an OA microenvironment in vitro models.The effects of DA on IL-1?-induced MMP-1?3?13 and Collagen II expression were detected by q RT-PCR(quantitative real time polymerase chain reaction)and Western blot analysis,as well as differences in GAGs(Glycosaminoglycans)deposition by cell safranin O staining.Western blot was used to detecte the protein level of i NOS(inducible nitric oxide synthase),COX-2(cyclooxygenase-2),the expression of NF-?B and JAK2 / STAT3 signaling pathways related proteins were detected by Western blot.3.C57BL/6 mice underwent DMM(destabilization of the medial meniscus)on knee joint to induce OA.The level of cartilage degeneration was evaluated using the Safranin O/Fast Green staining and OARSI(Osteoarthritis Research Society International)cartilage histopathology assessment system.Results 1.DA decreased MMP-1?MMP-3?MMP-13?i NOS?COX-2 expression and enhanced GAGs?Collagen II expression in IL-1?-stimulated chondrocytes.2.DA represses IL-1?-induced NF-?B and JAK2/STAT3 signaling pathways activation in chondrocytes.3.DA prevented the development of osteoarthritis in a mouse OA model.Conclusion 1.DA inhibits the expression of MMPs and related inflammatory factors in IL-1?-treated chondrocytes by regulating the NF-?B and JAK2/STAT3 signaling pathways.2.Inhibition of inflammation related signaling pathways in chondrocytes may be a novel therapeutic for OA treatment.