The Protective Effect And Its Correlated Molecular Mechanisms Of ?-receptor Blockers On Articular Cartilage

Osteoarthritis(OA)is a disease affecting hundreds of millions of people worldwide,which mainly manifestes as pain and dysfunction of the affected joints and seriously affects people's quality of life.Its pathologic progression mainly involves the degradation of articular cartilage,the irreversible articular cartilage damage leads to OA is still unable to be cured.There is growing evidence that the denaturation and degradation of extracellular matrix(ECM)generated by chondrocytes,especially collagen II(Col II)and Proteoglycans leads to the loss of cartilage integrity and strength is the most important pathologic features of osteoarthritis.The degradation of cartilage matrix is mainly mediated by a variety of cytokines and signaling pathways such as matrix metalloproteinases(MMPs),interleukin(IL)and nuclear factor kappa-B(NF-?B).Accordingly,the selection of an appropriate medicine as intervention targets is considered to be critical for ECM degradation and cartilage damage.Noteworthily,functioning as ?-adrenoceptor,P-blockers have also been reported to possess antioxidant properties of disposing and inhabiting Reactive oxygen species(ROS),thus protecting cardiovascular system,kidney and liver.Therefore,it is of significance to investigate the molecular biology mechanism for ?-blockers' potential effect on articular cartilage.Firstly,the concentration of IL-17,MMP-3 and Omentin-1 in serum and the articular synovial fluid of healthy people and OA patients are meansured by using enzyme-linked immunosorbent(ELISA),and the correlation between these factors and Western Ontario and McMaster university osteoarthritis index(WOMAC)score which represents of the severitydegree of OA are analyzed.The results domonstrate the expression of IL-17 and MMP-3 in serum and synovial fluid of OA patients are synchronous,and positively correlated with WOMAC total scores,suggesting that IL-17 and MMP-3 may circulate in arthrosis and blood circulation,leading to knee OA and other articular diseases.Besides,the concentration of Omentin-1 which can be expressed in chondrocyte,an adiponectin with anti-inflammatory property,is expressed in synovial fluid rather than serum of OA patients and exhibits negative correlation with WOMAC total scores,suggesting that Omentin-1 is confined in arthrosis without participating in the blood circulation.The positive correlation between the concentration of IL-17,MMP-3 and OA gravity,together with the negative correlation between Omentin-1 concentration and OA gravity,implies that these cell factors may serve as potential biomarkers to indicate the severity,progression and prognosis of OA,providing a reference for alternative medicine and treatment.Next,we clarify the molecular mechanism of carvedilol on Col II and proteoglycans degradation which caused MMPs expression mediated by IL-1?.Normal chondrocytes treated by IL-1? is a classical model for simulating OA chondrocytes in vitro.Our results suggest that treatment with carvedilol does not alter the expression of proteoglycan or Col II at the mRNA level in SW1353 chondrocytes.However,carvedilol is able to reverse the dose-dependent reversal of protein levels of proteoglycan and Col II caused by IL-1?.The inhibitory effect of carvedilol on proteoglycan and Col II expression is post-translational modification.In addition,carvedilol can reverse the mRNA and protein expression of MMP-1 and MMP-13 induced by IL-1? in SW1353 chondrocytes in a dose-dependent manner.Mechanistically,the effects of IL-1? on IKK-?/? phosphorylation and I?B-? degradation are inhibited in carvedilol pretreated SW1353 chondrocytes.Carvedilol suppresses IL-1?-induced NF-?B p65 translocation from the cytoplasm to the nucleus.Notably,luciferase reporter assay shows that carvedilol reverses the inhibition of IL-1? by a significant increase in NF-?B luciferase activity.In conclusion,carvedilol may be a potential therapeutic agent for cartilage protection.Finally,we elucidate the molecular mechanism of how another ?-blocker nebivolol blocks I?B-?/NF-1?B,STAT-1(signal transducers and activators of transcription)and IRF-1(interferon regulatory factor 1)signal pathway,and thus suppresses MMP-13 expression and type II collagen degradation.The experimental results indicate that nebivolol can inhibit the increase in mRNA as well as protein expression and activity of MMP-13 and degradation type II collagen induced by interleukin-1?.Importantly,nebivolol significantly reverses the level of type II collagen reduced by IL-1?.Besides,nebivolol is found to remit the increase in I?B?phosphorylation and decrease the expression of total I?B? which were induced by IL-1?,and then inhibit p65 nuclear translocation and NF-?B transcriptional activity.In addition,our results suggest that IL-1? treatment may result in a significant increase in expression of transcription factor-interferon regulatory factor-1(IRF-I)at mRNA and protein levels,which is significantly improved by treatment with nebivolol.The effect of signal transducers and activators of transcription 1(STAT1)on IRF-1 expression have also been shown to modulate by nebivolol.These results indicate that nebivolol can be used to inhabit the degradation of articular cartilage and embrace potential treatment of OA.In conclusion,the measurement involved cytokine concentrations of OA may serve as determinant biological index for the progress of disease,drug selection and treatment effectiveness of drug evaluation,provides specific values for the biological classification and early diagnosis standard of OA;Additionally,in vitro experiment results suggest that?-blockers may protect arthrodial cartilage,which provides theoretical basis for ?-blockers as OA therapeutic drug and shed light upon on OA biological treatment.