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Publications (3)37.52 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: PTH regulates transcription of a number of genes involved in bone remodeling and calcium homeostasis. We have previously shown that the matrix metalloproteinase-13 (MMP-13) gene is induced by PTH in osteoblastic cells as a secondary response through the protein kinase A pathway requiring the runt domain and activator protein 1 binding sites of the proximal promoter. Here, we investigated the changes PTH causes in histone acetylation in this region (which contains the only deoxyribonuclease-hypersensitive sites in the promoter) leading to MMP-13 gene activation in these cells. Chromatin immunoprecipitation experiments revealed that PTH rapidly increased histone H4 acetylation followed by histone H3 acetylation associated with the different regions of the MMP-13 proximal promoter. The hormone also stimulated p300 histone acetyl transferase activity and increased p300 bound to the MMP-13 proximal promoter, and this required protein synthesis. Upon PTH treatment, Runx2, already bound to the runt domain site of the MMP-13 promoter, interacted with p300, which then acetylated histones H4 and H3. The knockdown of either Runx2 or p300 by RNA interference reduced PTH-induced acetylation of histones H3 and H4, association of p300 with the MMP-13 promoter, and resultant MMP-13 gene transcription. Overall, our studies suggest that without altering the gross chromatin structure, PTH stimulates acetylation of histones H3 and H4 via recruitment of p300 to Runx2 bound to the MMP-13 promoter, resulting in gene activation. This work establishes the molecular basis of transcriptional regulation in osteoblasts by PTH, a hormone acting through a G-protein coupled receptor.
    No preview · Article · Jun 2009 · Molecular Endocrinology
  • Christine E Boumah · Nagarajan Selvamurugan · Nicola C Partridge
    [Show abstract] [Hide abstract] ABSTRACT: The osteoblast is a cell of mesenchymal origin sharing a common progenitor stem cell with chondrocytes, myoblasts, and bone marrow stromal cells including adipocytes. Preosteoblasts, however, are capable of responding to a variety of extracellular signaling pathways and further differentiating into bone-lining mature osteoblasts and osteocytes; this process of osteoblast differentiation or osteogenesis, crucial for skeletal tissue formation, repair, and maintainance, is under extensive investigation. Osteoblast differentiation is often subdivided into three stages: (1) a proliferation stage, during which the cells exit from the cell cycle and fully commit to the osteoblast phenotype; in this stage, the osteoblasts express high levels of immediate early genes (c-fos, c-jun, c-myc), histones, cyclins, and several other genes specific to proliferating cells (1-3); (2) a growth arrest stage, accompanied by development and maturation of extracellular matrix, downregulation of growth-associated genes, and expression of high levels of alkaline phosphatase and collagen (4, 5); and (3) a mineralization stage, with maximal osteoblastic expression of extracellular matrix components including noncollagenous bone matrix proteins such as osteocalcin, osteopontin, and bone sialoprotein (4, 6, 7). Osteoblast differentiation and the mechanisms responsible for the temporal and sequential display of distinct subsets of transcriptionally active osteoblastic genes were established using in vitro osteoblast culture models and, more recently, in in vivo studies with mice. Osteoblast activities are regulated, in a stage-specific manner, by hormones including parathyroid hormone (PTH) (8, 9), 1,25(OH)2 vitamin D3 (10), estrogen (11, 12), and glucocorticoids (13, 14). Osteoblast differentiation is also regulated by cytokines and various local factors such as transforming growth factor-beta (TGF-β) (15, 16) and fibroblast growth factor (17).
    No preview · Article · Feb 2005 · Progress in Nucleic Acid Research and Molecular Biology
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    [Show abstract] [Hide abstract] ABSTRACT: The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families1, 2. We localized the disease gene to 16q12−21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.
    Full-text · Article · Jun 2001 · Nature Genetics