Parathyroid hormone (PTH) is an essential regulator of calcium homeostasis and also has a role as an anabolic hormone for bone. PTH induces matrix metalloproteinase-13 (MMP-13) gene transcription in osteoblastic cells through a cAMP-dependent pathway requiring de novo protein synthesis, i.e., this is a secondary event. We have identified the PTH-response elements as being the runt domain and the activator protein-1 binding sites in the MMP-13 promoter. We have demonstrated a PTH-dependent cooperative interaction between the sites and the proteins (Runx2 and Fos/Jun) binding to them. We have now established that these two sites in the MMP-13 promoter are in a single nucleosome close to the TATA box and PTH relaxes and modifies this nucleosome but does not cause its dissociation. The relaxation is the product of several steps which occur as early and late events: In the early events, first, PTH stimulates p300 (a histone acetyltransferase, HAT) activity, causes the phosphorylation of Runx2, and p300 is recruited to the promoter resulting in early site-specific acetylation of histone H4;in the late events, newly synthesized Fos/Jun associate with the promoter and then appear to interact with Runx2 followed by recruitment of CBP (CREB binding protein), another HAT, to the entire proximal promoter and acetylation of histone H3 resulting in loosening of the nucleosome. Maximal transcription of the MMP-13 gene then ensues. Our hypothesis is that the gene is in a repressed state and PTH causes the stepwise modification of the chromatin though dissociation of histone deacetylases and co-repressor proteins and association of HATs and activator proteins. The long-term goals of this work are to delineate the mechanisms conveying PTH action to regulation of transcription of the MMP-13 gene in osteoblasts. Consequently, the specific aims of this competing continuation proposal are to, 1) investigate the early events at the RD site of the MMP-13 promoter, and, 2) investigate the late events at the AP-1 site and the interaction of Fos/Jun with other proteins on the MMP-13 promoter. The results of this work will make major contributions to our knowledge of how PTH exerts its nuclear effects on osteoblast function. In so doing, the data will also provide new perspectives into treatment of disorders of calcium metabolism. This research will investigate how a protein hormone (parathyroid hormone, PTH) is able to interact with a cell's surface and transmit signals to the nucleus to cause the DMAand associated proteins to change their structure and cause expression of an enzyme involved in bone breakdown. PTH is essential for regulating serum calcium levels, and is also being used to treat osteoporosis. The results of our research could lead to new drugs being developed, in place of PTH, to treat osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK047420-17S1
Application #
7989030
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2010-04-07
Project End
2010-06-30
Budget Start
2010-04-07
Budget End
2010-06-30
Support Year
17
Fiscal Year
2010
Total Cost
$57,000
Indirect Cost
Name
New York University
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Ricarte, Florante R; Le Henaff, Carole; Kolupaeva, Victoria G et al. (2018) Parathyroid hormone(1-34) and its analogs differentially modulate osteoblastic Rankl expression via PKA/SIK2/SIK3 and PP1/PP2A-CRTC3 signaling. J Biol Chem 293:20200-20213
Nakatani, Teruyo; Partridge, Nicola C (2017) MEF2C Interacts With c-FOS in PTH-Stimulated Mmp13 Gene Expression in Osteoblastic Cells. Endocrinology 158:3778-3791
Siddiqui, Jawed A; Johnson, Joshua; Le Henaff, Carole et al. (2017) Catabolic Effects of Human PTH (1-34) on Bone: Requirement of Monocyte Chemoattractant Protein-1 in Murine Model of Hyperparathyroidism. Sci Rep 7:15300
Nakatani, Teruyo; Chen, Tiffany; Partridge, Nicola C (2016) MMP-13 is one of the critical mediators of the effect of HDAC4 deletion on the skeleton. Bone 90:142-51
Ricarte, Florante; Nakatani, Teruyo; Partridge, Nicola (2016) PTH Signaling and Epigenetic Control of Bone Remodeling. Curr Mol Biol Rep 2:55-61
Liu, Zhongbo; Kennedy, Oran D; Cardoso, Luis et al. (2016) DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH. FASEB J 30:635-52
Fei, Yurong; Shimizu, Emi; McBurney, Michael W et al. (2015) Sirtuin 1 is a negative regulator of parathyroid hormone stimulation of matrix metalloproteinase 13 expression in osteoblastic cells: role of sirtuin 1 in the action of PTH on osteoblasts. J Biol Chem 290:8373-82
Vimalraj, S; Partridge, Nicola C; Selvamurugan, N (2014) A positive role of microRNA-15b on regulation of osteoblast differentiation. J Cell Physiol 229:1236-44
Shimizu, Emi; Nakatani, Teruyo; He, Zhiming et al. (2014) Parathyroid hormone regulates histone deacetylase (HDAC) 4 through protein kinase A-mediated phosphorylation and dephosphorylation in osteoblastic cells. J Biol Chem 289:21340-50
Huang, Xi; Xu, Youjia; Partridge, Nicola C (2013) Dancing with sex hormones, could iron contribute to the gender difference in osteoporosis? Bone 55:458-60

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