Parathyroid hormone activation of matrix metalloproteinase-13 transcription requires the histone acetyltransferase activity of p300 and PCAF and p300-dependent acetylation of PCAF.
Parathyroid hormone (PTH) regulates the transcription of many genes involved in bone remodeling in osteoblasts. One of these genes is matrix metalloproteinase-13 (MMP-13), which is involved in bone remodeling and early stages of endochondral bone formation. We have previously shown that Mmp-13 gene expression is highly induced by PTH treatment in osteoblastic UMR 106-01 cells, as well as primary osteoblasts. Here, we show that p300/CBP-associated factor (PCAF), in addition to p300 and Runx2, is required for PTH activation of Mmp-13 transcription. PCAF was increasingly recruited to the MMP-13 proximal promoter region after PTH treatment, and this was associated with an increase in RNA polymerase II recruitment and histone acetylation. In addition, PTH treatment increased the acetylation of PCAF, a process that required p300. Knockdown of PCAF, p300, or Runx2 by siRNA decreased Mmp-13 mRNA expression after PTH treatment in both UMR 106-01 cells and primary osteoblasts. We found that there is a mutual dependence between p300 and PCAF to be recruited to the Mmp-13 promoter after PTH treatment. In promoter-reporter assays, p300 and PCAF had an additive effect on PTH stimulation of MMP-13 promoter activity, and this required their histone acetyltransferase activity. Our findings demonstrate that PCAF acts downstream of PTH signaling as a transcriptional coactivator that is required for PTH stimulation of MMP-13 transcription. PCAF cooperates with p300 and Runx2 to mediate PTH activation of MMP-13 transcription.
Lee
Minnkyong
M
Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
Partridge
Nicola C
NC
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D050659:Core Binding Factor Alpha 1 Subunit; D050881:E1A-Associated p300 Protein; D053509:Matrix Metalloproteinase 13; D010281:Parathyroid Hormone; D012319:RNA Polymerase II; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493717:Runx2 protein, rat; C494362:Ep300 protein, rat; C507083:Mmp13 protein, rat