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miR‐873‐3p targets HDAC4 to stimulate matrix metalloproteinase‐13 expression upon parathyroid hormone exposure in rat osteoblasts
Author(s) -
Malavika Desai,
Shreya Srinivasan,
Raj Priya Vembar,
Rohini Muthukumar,
He Zhiming,
Partridge Nicola C.,
Selvamurugan Nagarajan
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29454
Subject(s) - runx2 , hdac4 , corepressor , parathyroid hormone , microrna , gene silencing , chemistry , microbiology and biotechnology , transcription factor , downregulation and upregulation , osteoblast , cancer research , biology , medicine , histone deacetylase , repressor , gene , biochemistry , histone , calcium , organic chemistry , in vitro
Matrix metalloproteinase‐13 (MMP‐13) plays a predominant role in endochondral bone formation and bone remodeling. Parathyroid hormone (PTH) stimulates the expression of MMP‐13 via Runx2, a bone transcription factor in rat osteoblastic cells (UMR106‐01), and histone deacetylase 4 (HDAC4) acts as a corepressor of Runx2. Moreover, microRNAs (miRNAs) play an important role in regulating genes posttranscriptionally. Here, we hypothesized that PTH upregulates the miRNAs targeting HDAC4, which could lead to increased Runx2 activity and MMP‐13 expression in rat osteoblastic cells. We identified several miRNAs that putatively target rat HDAC4 using bioinformatics tools. miR‐873‐3p was significantly upregulated by PTH in rat osteoblasts. miR‐873‐3p overexpression downregulated HDAC4 protein expression, increased Runx2 binding at the MMP‐13 promoter, and increased MMP‐13 messenger RNA expression in UMR106‐01 cells. A luciferase reporter assay identified the direct targeting of miR‐873‐3p at the 3′‐untranslated region of HDAC4. Thus, miR‐873‐3p targeted HDAC4 and relieved the corepressor effect of HDAC4 on Runx2 for MMP‐13 expression in rat osteoblasts. This study advances our knowledge of posttranscriptional gene regulation occurring in bone and bone‐related diseases and clarifies the role of miRNAs as diagnostic biomarkers.