HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression.
Parathyroid hormone (PTH) is a hormone regulating bone remodeling through its actions on both bone formation and bone resorption. Previously we reported that PTH induces matrix metalloproteinase-13 (MMP-13) transcription in osteoblastic cells. Here, we show that histone deacetylase 4 (HDAC4) interacts with Runx2, binds the MMP-13 promoter, and suppresses MMP-13 gene transcription in the rat osteoblastic cell line, UMR 106-01. PTH induces the rapid cAMP-dependent protein kinase-dependent release of HDAC4 from the MMP-13 promoter and subsequent transcription of MMP-13. Knock-out of HDAC4 either by siRNA in vitro or by gene deletion in vivo leads to an increase in MMP-13 expression, and overexpression of HDAC4 decreases the PTH induction of MMP-13. All of these observations indicate that HDAC4 represses MMP-13 gene transcription in bone. Moreover, PTH stimulates HDAC4 gene expression and enzymatic activity at times corresponding to the reassociation of HDAC4 with the MMP-13 promoter and a decline in its transcription. Thus, HDAC4 is a basal repressor of MMP-13 transcription, and PTH regulates HDAC4 to control MMP-13 promoter activity. These data identify a novel and discrete mechanism of regulating HDAC4 levels and, subsequently, gene expression.
Shimizu
Emi
E
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010.
Selvamurugan
Nagarajan
N
Department of Biotechnology, School of Bioengineering, Sri Ramaswamy Memorial University, Kattankulathur 603 203, Tamil Nadu, India.
Westendorf
Jennifer J
JJ
Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905.
Olson
Eric N
EN
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Partridge
Nicola C
NC
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010. Electronic address: ncp234@nyu.edu.
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D045744:Cell Line, Tumor; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000201:enzymology* / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
D010281:Parathyroid Hormone; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D053509:Matrix Metalloproteinase 13; C400300:HDAC4 protein, human; D006655:Histone Deacetylases