Abstract
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.
Highlights
PTH2 is a peptide hormone that plays a central role in regulating serum ion concentrations
p300/CBP-associated factor (PCAF) Is Recruited to the matrix metalloproteinase-13 (MMP-13) Proximal Promoter Region with Parathyroid hormone (PTH) Treatment—Previous work from our laboratory has shown that p300 is recruited to the Mmp-13 proximal promoter region after PTH treatment in osteoblastic UMR 106-01 cells [23]
In the process of identifying another candidate that could be responsible for the increase in HAT activity, we found that PCAF, another well defined HAT, coimmunoprecipitated with p300 in UMR 106-01 cells with and without PTH treatment (Fig. 1A)
Summary
PTH2 is a peptide hormone that plays a central role in regulating serum ion concentrations. 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.
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