Intermittent administration of parathyroid hormone (PTH) increases bone mass, at least in part, by increasing osteoblast number. One possible source of osteoblasts might be conversion of inactive lining cells to osteoblasts, and indirect evidence is consistent with this hypothesis. To better understand the possible effect of PTH on lining cell activation, a lineage tracing study was conducted using an inducible gene system. Dmp1-CreERt2 mice were crossed with ROSA26R reporter mice to render targeted mature osteoblasts and their descendents, lining cells and osteocytes, detectable by X-gal staining. Dmp1-CreERt2(+):ROSA26R mice were injected with 0.25 mg 4-OH-tamoxifen (4-OHTam) on postnatal day 3, 5, 7, 14, and 21. The animals were sacrificed on postnatal day 23, 33 or 43 (2, 12 or 22 days after the last 4-OHTam injection). On day 43, mice were challenged with a subcutaneous injection of human PTH (1–34, 80 μg/kg) or vehicle once daily for 3 days. By 22 days after the last 4-OHTam injection, most X-gal (+) cells on the periosteal surfaces of both the calvaria and tibia were flat. Moreover, bone formation rate and collagen I(α1) mRNA expression were decreased at day 43 compared to day 23. After 3 days of PTH injections, the thickness of X-gal (+) cells increased, as did their expression of osteocalcin and collagen I(α1) mRNA. Electron microscopy revealed X-gal-associated chromagen particles in both thin cells prior to PTH administration and cuboidal cells following PTH administration. These data support the hypothesis that intermittent PTH treatment can increase osteoblast number by converting lining cells to mature osteoblasts in vivo.
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. The transition from chemotherapy-responsive breast cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multidrug resistanceassociated proteins (MRPs). In this study, it was found that TAM-resistant MCF-7 (TAMR-MCF-7) cells expressed higher levels of MRP2 than control MCF-7 cells. Molecular analyses using MRP2 gene promoters supported the involvement of the pregnane X receptor (PXR) in MRP2 overexpression in TAMR-MCF-7 cells. Although CCAAT/enhancer-binding protein b was overexpressed continuously in TAMR-MCF-7 cells, this might not be responsible for the transcriptional activation of the MRP2 gene. In addition, the basal activities of phosphatidylinositol 3-kinase (PI3-kinase) were higher in the TAMR-MCF-7 cells than in the control cells. The inhibition of PI3-kinase significantly reduced both the PXR activity and MRP2 expression in TAMR-MCF-7 cells. Overall, MRP2 induction plays a role in the additional acquisition of chemotherapy resistance in TAM-resistant breast cancer.
Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α 1 (MATα1) have lower PHB1 expression and we reported c-MYC interacts directly with both proteins. Furthermore, c-MYC and MATα1 expert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1 and c-MYC and PHB1's role in liver tumorigenesis. We found PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1's expression correlate inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c-MYC, MAFG and c-MAF. Both PHB1 and MATα1 heterodimerize with MAX, bind to the E-box element and repress E-box promoter activity. PHB1 promoter contains a repressive E-box element, is occupied mainly by MAX, MNT and MATα1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c-MYC, c-MAF and MAFG in cancer cells and human HCC/CCA. All 8-month old liver-specific Phb1 knockout mice developed HCC and one developed CCA. 5-month old Phb1 heterozygotes but not Phb1 flox mice developed aberrant bile duct proliferation and one developed CCA 3.5 months after left and median bile duct ligation (LMBDL). Phb1 heterozygotes had a more profound fall in the expression of GSH synthetic enzymes and higher hepatic oxidative stress following LMBDL. Conclusion We have identified PHB1, down-regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E-box. PHB1 positively regulates MAT1A while suppressing c-MYC, MAFG and c-MAF expression. In mice, reduced PHB1 expression predisposes to the development of cholestasis-induced CCA.
Cyclooxygenase-2 (COX-2) is a key enzyme involved in the inflammatory process that is rapidly induced in macrophages in response to LPS. Carbon monoxide (CO), a byproduct of heme oxygnease-1, can suppress proinflammatory response in various in vitro and in vivo models of inflammation. This study was undertaken to examine whether CO can regulate (and if so, to delineate the mechanism by which CO regulates) LPS-induced COX-2 expression in macrophages. RAW 264.7 murine macrophages were stimulated with LPS (0-10 ng/ml) with or without CO (500 ppm). Northern and Western blot analysis was done. Progstaglandin E 2 and nitrite concentration was measured from cell culture supernatant. Electrophoretic mobility shift assay was performed to assess nuclear factor binding. CO downregulated LPS-induced COX-2 mRNA and protein expression. CO also inhibited LPS-induced prostaglandin E 2 secretion (P Ͻ 0.05). CO also decreased LPS-induced CCAAT/enhancer-binding protein (C/EBP)  and ␦ protein expression in LPS-treated RAW 264.7 cells. Gel shift analysis revealed that CO treatment decreased LPSinduced activation of protein binding to C/EBP consensus oligonucleotides of murine cyclooxygenase-2 promoter. CO also decreased LPS-induced nitric oxide synthase-2 protein expression and nitrite production, and decreased LPS-induced activation of protein binding to C/EBP consensus oligonucleotides of murine nitric oxide synthase-2 promoter. CO may act as an important regulator of inflammation by virtue of its ability to regulate C/EBPs. Keywords: heme oxygenase; lipopolysaccharides; nitric oxide synthase Heme oxygenase-1 (HO-1) is a microsomal enzyme responsible for degradation of heme, generating biliverdin, iron, and carbon monoxide (CO) (1). HO-1 can be induced by a wide variety of stimuli, and the enzyme is involved in cellular and tissue defense against oxidative stress possessing potent anti-inflammatory properties (2, 3). There is growing interest in the role of CO in the anti-inflammatory and cytoprotective function of HO-1 (4-7), but the pathways involved in the anti-inflammatory effect of CO are poorly understood. CO can modulate mitogen-activated protein kinase (5) and guanylate cyclase/3Ј,5Ј-guanylate cyclic monophospate (cGMP) pathway (8) to inhibit secretion of proinflammatory cytokines. CO also modulates several transcription factors, including NF-B (4, 6) and activating protein-1 (4), which are involved in inflammation. But whether other pathways or molecules are involved in the anti-inflammatory effect of CO is not known.
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