title: MicroRNA-381 Regulates Chondrocyte Hypertrophy by Inhibiting Histone Deacetylase 4 Expression.
abstract: Chondrocyte hypertrophy, regulated by Runt-related transcription factor 2 (RUNX2) and matrix metalloproteinase 13 (MMP13), is a crucial step in cartilage degeneration and osteoarthritis (OA) pathogenesis. We previously demonstrated that microRNA-381 (miR-381) promotes MMP13 expression during chondrogenesis and contributes to cartilage degeneration; however, the mechanism underlying this process remained unclear. In this study, we observed divergent expression of miR-381 and histone deacetylase 4 (HDAC4), an enzyme that directly inhibits RUNX2 and MMP13 expression, during late-stage chondrogenesis of ATDC5 cells, as well as in prehypertrophic and hypertrophic chondrocytes during long bone development in E16.5 mouse embryos. We therefore investigated whether this miRNA regulates HDAC4 expression during chondrogenesis. Notably, overexpression of miR-381 inhibited HDAC4 expression but promoted RUNX2 expression. Moreover, transfection of SW1353 cells with an miR-381 mimic suppressed the activity of a reporter construct containing the 3'-untranslated region (3'-UTR) of HDAC4. Conversely, treatment with a miR-381 inhibitor yielded increased HDAC4 expression and decreased RUNX2 expression. Lastly, knockdown of HDAC4 expression resulted in increased RUNX2 and MMP13 expression in SW1353 cells. Collectively, our results indicate that miR-381 epigenetically regulates MMP13 and RUNX2 expression via targeting of HDAC4, thereby suggesting the possibilities of inhibiting miR-381 to control chondrocyte hypertrophy and cartilage degeneration.
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. chenweishen5@163.com.
authors: Weishen
authors: W
authors: Chen
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. shengpuyi@hotmail.com.
authors: Puyi
authors: P
authors: Sheng
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. wongchiyue@163.com.
authors: Zhiyu
authors: Z
authors: Huang
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. fanfan71@126.com.
authors: Fangang
authors: F
authors: Meng
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. neokang@163.com.
authors: Yan
authors: Y
authors: Kang
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. huangguang06@163.com.
authors: Guangxin
authors: G
authors: Huang
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. zhzhiqi@163.com.
authors: Zhiqi
authors: Z
authors: Zhang
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. liaowmsysu@163.com.
authors: Weiming
authors: W
authors: Liao
authors: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. zhangziji@mail.sysu.edu.cn.
authors: Ziji
authors: Z
authors: Zhang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D050659:Core Binding Factor Alpha 1 Subunit; D035683:MicroRNAs; D053509:Matrix Metalloproteinase 13; D006655:Histone Deacetylases
keywords: Runt-related transcription factor 2; chondrocyte hypertrophy; histone deacetylase 4; matrix metalloproteinase 13; microRNA-381