The Function And Mechanism Of Histone Deacetylase 4 In Age-related Osteoarthritis

Objective:In this study we will observe the OA change and the HDAC4 expression in human cartilage.In order to understand the function and the mechanism of HDAC4 in OA,we exam the mouse knee OA by conditional knock out the HDAC4 gene using gene knock out mice.Methods:1.Safranin O staining was used to evaluate the degeneration of human tibial plateau cartilage.The different HDAC4 expression in human OA and normal cartilage were observed using immunohistochemical staining.2.The Agg^{tm（IRES-CreERT2）};HDAC4^fl/fl gene mice were reproducted.Fourty Agg^{tm（IRES-CreERT2）};HDAC4^fl/fl mouse were divided into TM group（n=20）and NO TM（n=20）.The HDAC4^fl/fl mouse（n=20）is used as TM control.The TM will be injected as 1mg/0.01kg/day for 5 consist days in TM and TM control group at two month old.The oil will be injected as the same dose and way as TM in NO TM group.The mouse moves freely after the injection.The degeneration of the 8 month old mouse knee cartilage were visualized by Safrainin O staining and quantified by OARSI score.The expression of HDAC4、Agg、Col II、Runx2、Sox-9、Col X、Ihh and MMP-13 were observed using immunohistochemical staining.And the relative mRNA level of HDAC4、Agg、Col II、Runx2、Sox-9、Col X、Ihh、MMP-13、PTHrP and Gli1 were tested by Rt-PCR.Results:1.The HDAC4 is mainly expressed in hypertrophic chondrocyte.The HDAC4expressions is reduced in knee OA patients’hypertrophic chondrocyte.2.The Safranin O staining results showed that the degeneration of cartilage in 8month old mouse were observed in TM group,while the NO TM group hasn’t show any lesion.The OARSI score of TM group was significantly higher than the other groups.Immunohistochemical staining results shows that the expression of Runx-2、MMP-13、Ihh、Collagen X is increased in TM group compared to the NO TM group while the Collagen II、Aggrecan、Sox-9 expression is significantly decreased.The Rt-PCR results shows the same tend with the Immunohistochemical staining results,beside,the relative mRNA level of PTHrP is increased while Gli1 is decreased.Conclusion:The HDAC4 is mainly expressed in hypertrophic chondrocyte.The expression of HDAC4 in knee OA hypertrophic chondrocyte is decreased.The decrease of HDAC4may accelerate the onset of OA through speeding up the chondrocyte hypertrophy.