Disease relevance of Bglap2

• Histomorphometric studies done before and after ovariectomy showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption [1].
• While osteocalcin-deficient mice have increased bone formation, MGP-deficient mice have abnormal calcification leading to osteopenia, fractures, and premature death owing to arterial calcification [2].
• Osteocalcin promoter-based toxic gene therapy for the treatment of osteosarcoma in experimental models [3].
• The runt domain site is identical to an osteoblast-specific element-2 or acute myelogenous leukemia binding sequence in the mouse and rat osteocalcin genes, respectively [4].
• RESULTS: GH tg mice displayed a significant increase in body weight (up to 50%) and BMC (up to 90%), but serum osteocalcin was significantly reduced compared with controls [5].

High impact information on Bglap2

• Although immature osteoblasts, which expressed alkaline phophatase weakly but not Osteopontin and Osteocalcin, and a few immature osteoclasts appeared at the perichondrial region, neither vascular nor mesenchymal cell invasion was observed in the cartilage [6].
• To our knowledge, this study provides the first evidence that osteocalcin is a determinant of bone formation [1].
• Transgenic mice overexpressing FIAT in osteoblasts also had reduced osteocalcin gene expression and decreased bone mineral density, bone volume, mineralized volume, trabecular thickness, trabecular number, and decreased rigidity of long bones [7].
• Long bones of fra-1(delta/delta) mice appear to have normal osteoclasts but express reduced amounts of bone matrix components produced by osteoblasts and chondrocytes such as osteocalcin, collagen1a2 and matrix Gla protein [8].
• The production of these MMPs is concomitant with the development of an RA-induced differentiation program characterized by formation of a mineralized bone matrix, downregulation of chondrocyte markers like type II collagen, and upregulation of osteoblastic markers such as osteocalcin [9].

Chemical compound and disease context of Bglap2

• Surprisingly, serum osteocalcin levels, a biochemical marker of bone formation, suggested that the bone-sparing effects of IL-7 neutralization were due not only to inhibition of bone resorption, but also to stimulation of bone formation [10].
• Osteosarcoma tumor growth was inhibited more efficiently than by either Ad-OC-TK plus ACV (P < 0.05) or MTX treatment (P < 0.005) alone [11].
• Chemogene therapy: osteocalcin promoter-based suicide gene therapy in combination with methotrexate in a murine osteosarcoma model [11].
• The discovery of OC expression in prostate cancer specimens led us to study the regulation of OC gene in androgen-independent metastatic human prostate PC3 cells [12].
• This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel [13].

Biological context of Bglap2

• From sequence inspection, DNA transfection experiments, and DNA binding assays, we could not identify a functional vitamin D-responsive element in the promoter of OG2 or in the first 3.3 kilobases of the OG1 promoter [14].
• Furthermore, during embryogenesis, OG1 and OG2 begin to be expressed at day 15.5, while ORG is transcribed as early as day 10 [15].
• We examine Osc expression by in situ hybridization during murine development, detailing temporospatial relationships with Msx2 expression during preappositional and appositional odontogenesis and calvarial osteogenesis [16].
• Northern blot analysis revealed that in the Ad/PDGF-A treated implants OPN was increased, whereas OC gene expression was downregulated at 3 weeks [17].
• On the other hand, Ad/PDGF-1308 inhibited mineralization of tissue-engineered cementum possibly due to the observed downregulation of BSP and OC and a persistence of stimulation of MNGCs [17].

Anatomical context of Bglap2

• However, we show that 1,25-(OH)2D3 treatment of primary osteoblasts abolishes the binding of OSF2, an osteoblast-specific activator of transcription that binds to OSE2, a critical osteoblast-specific cis-acting element present in OG1 and OG2 promoters [14].
• Osteocalcin was expressed specifically by osteoblasts in the developing metatarsals [18].
• Osn and Osc mRNA, which localized in osteoblasts and odontoblasts, were also detected in the cells of odontoma-like masses in mi/mi mice [19].
• Minimal difference in OC expression was observed between juvenile and adult dura mater [20].
• This study examined the effect of PTH on mouse osteocalcin gene expression in MC3T3-E1 preosteoblastic cells and primary cultures of bone marrow stromal cells [21].

Associations of Bglap2 with chemical compounds

• Consistent with these DNA binding data, a mutation in OSE2 in the OG2 promoter abrogated the inhibitory effect of 1,25-(OH)2D3 treatment on this promoter activity [14].
• Osteocalcin and osteopontin are noncollagenous proteins secreted by osteoblasts and regulated by a complex interplay of systemic and locally produced factors, including growth factors and steroid hormones [22].
• Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells [23].
• Here, we examined the mRNA expressions of OPN, MGP, ON, and OC in the kidneys of stone-forming model rats administered an oxalate precursor, ethylene glycol (EG) for up to 28 days [24].
• However, when cells were treated acutely with 1,25(OH)2D3 at later times during growth in ascorbic acid, the induction of mouse osteocalcin protein was only partially inhibited [25].

Regulatory relationships of Bglap2

• Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors [26].
• This member of the runt/Cbfa family of transcription factors was first identified as the nuclear protein binding to an osteoblast-specific cis-acting element activating the expression of Osteocalcin, the most osteoblast-specific gene [27].
• Therefore, KCA-098 had a bidirectional effect on the differentiation of osteoblasts (i.e., stimulating both alkaline phosphatase activity and synthesis of CDP and inhibiting osteocalcin synthesis) [28].

Other interactions of Bglap2

• We named them osteocalcin gene 1 (OG1), osteocalcin gene 2 (OG2), and osteocalcin-related gene (ORG) in order from the 5' end to the 3' end of the cluster [15].
• Collectively, these studies establish that actions of PTH on the osteocalcin gene are mediated by multiple signaling pathways and require OSE1 and associated nuclear proteins [21].
• Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts [29].
• Incubating primary muscle cells with 300 ng/ml of BMP-2 for 6 d also inhibited myotube formation, whereas induced ALP activity and osteocalcin production [30].
• OG2 Phex transgenic Hyp mice did exhibit a small, but significant, increase in bone mineral density and dry ashed weight, suggesting a partial mineralization effect from restoration of Phex function in mature osteoblasts [31].

Analytical, diagnostic and therapeutic context of Bglap2

• The mRNA expression of alkaline phosphatase and osteocalcin was increased by SFs from patients with OA, whereas only osteocalcin mRNA was increased by SFs from patients with a loose prosthesis [32].
• Here we show that OSE1 is a cis-acting element as important as OSE2 for the osteoblast-specific expression of OG2 in cell culture and transgenic mice [33].
• Southern blot analysis and restriction mapping of genomic DNA from several strains of mice indicated the presence of at least three copies of the OC coding sequence within a 19 kb fragment [34].
• Finally, chromatin immunoprecipitation analysis in MC3T3-E1 cells showed in vivo occupancy of the OG2 promoter by Runx2 and C/EBPdelta [35].
• Our results revealed that reduced Nurr1 expression, using Nurr1 siRNA in MC3T3-E1 cells, affected the expression of osteoblast differentiation marker genes, osteocalcin (OCN) and collagen type I alpha 1 (COL1A1), as measured by quantitative real-time PCR [36].

References