Inhibition Of Taxol Against Angiogenesis In Collagen-induced Arthritis Mouse Model

BackgroundAngiogenesis is one of the critical features in rheumatoid arthritis(RA),and it plays an indispensable role in pannus formation and progression in RA.Uncontrolled neovascularization could help the infiltration of inflammatory cells and lead to synovial hyperplasia and the progressive destruction of bone and cartilage.Collagen-induced arthritis(CIA)is an ideal model of RA,it shares a number of clinical,histological and immunological feature with RA.Precious studies demonstrated that the taxol(PTX)has anti-angiogenesis effects.However,it is unkown that if PTX has the function of anti-angiogenesis in RA.ObjectiveTo evaluate the inhibitory effects of taxol(PTX)on angiogenesis and the expression of VEGF?HIF-1? in CIA mouse model.MethodsA total of 50 C57BL/6(H-2b)mice were used to induce a CIA mouse model with collagen ?(C?)and complete Freund's adjuvant(CFA).CIA mouse were randomly divided into four groups:CIA model group,PTX 1.5 mg/kg group,PTX 1.0 mg/kg group,PTX 0.5 mg/kg group,which the arthritic scores were more than 4 point,each group has six mice.In addition,6 normal mice were regarded as the control group.PTX was administered by intraperitoneal injection in the PTX treatment groups 8 times every other day.The normal control group and CIA model group received the same dosage solvent on alternate days.Arthritis index scores,tissue pathology scores after HE staining and synovium microvessel density(MVD)analysis after immunohistochemical(IHC)staining were performed.Immunohistochemistry and ELISA were used to detect the expression of vascular endothelial growth factor(VEGF)and hypoxia-inducible factor-a(HIF-1 a).Additionally,the correlation between MVD and pathological scores,level of VEGF and HIF-1 a in the synovium were also evaluated.ResultsAfter PTX treatment,the three intervention group arthritis index scores(1.33±0.52,2.00±0.63,3.33±1.03)declined when compared with the CIA group(5.67±1.03,P<0.001,P<0.001,P=0.016).The total histological scores in the three PTX treatment groups(2.50±0.66,3.89±0.86,3.89±0.86)were lower than those in the CIA group(7.67±0.79,P<0.001,P<0.001,P=0.007).Similarly,PTX significantly alleviated the scores for synovitis,pannus formation and bone destruction.Compared with the CIA group(110.32±5.06/mm2),the MVD of the three intervention groups decreased in dose-dependent manner(17.05±1.97/mm2,34.73±2.36/mm2,57.55±2.72/mm2;P<0.001,respectively).PTX reduced the expression of VEGF in three PTX treatment groups(42.38±3.22,74.30±4.14,121.69±3.81)compared with the CIA group(156.22±4.75;P<0.001,respectively).The level of HIF-la in the PTX 1.5 mg/kg and 1.0 mg/kg groups(19.93±2.92,31.99±5.60)was also weakened when compared with the CIA group(51.10±2.86;P<0.001,P<0.001).The levels of serum VEGF in the three treatment groups were 10.70±1.21 pg/ml,14.75±0.96 pg/ml,and 16.55±1.47 pg/ml,and the serum HIF-1? levels were 2.17±0.43 pg/ml,3.47±0.51 pg/ml,and 5.07±1.19 pg/ml.When compared with the CIA group(16.401±1.43 pg/ml,5.79±0.89 pg/ml),the levels of serum VEGF and HIF-la declined in the PTX 1.5 mg/kg(P<0.001,P<0.001)and PTX 1.0 mg/kg groups(P<0.001,P=0.032).Further analysis showed that MVD and pathological scores and levels of VEGF and HIF-1?in the synovium were positively correlated(r=0.921,r=0.944,r=0.889,r=0.969,r=0.933;P<0.001,respectively).ConclusionPTX can alleviate CIA by suppressing angiogenesis and it also can decrease the expression of VEGF and HIF-1? in CIA model,VEGF and HIF-1? may be the target for PTX suppression of microvessel formation.