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1.
Endocrinology ; 143(9): 3681-90, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12193584

ABSTRACT

Fish stanniocalcin (STC) inhibits uptake of calcium and stimulates phosphate reabsorption. To determine the role of the highly homologous mammalian protein, STC-1, we created and characterized transgenic mice that express STC-1 under control of a muscle-specific promoter. STC-1 transgenic mice were smaller than wild-type littermates and had normal growth plate cartilage morphology but increased cartilage matrix synthesis. In STC-1 mice, the rate of bone formation, but not bone mineralization, was decreased. Increased cortical bone thickness and changes in trabeculae number, density, and thickness in STC-1 mice indicated a concomitant suppression of osteoclast activity, which was supported by microcomputed tomography analyses and histochemistry. Skeletal muscles were disproportionately small and showed altered function and response to injury in STC-1 mice. Electron microscopy indicated that muscle mitochondria were dramatically enlarged in STC-1 mice. These changes in STC-1 mice could not be explained by deficits in blood vessel formation, as vascularity in organs and skeletal tissues was increased as was induction of vascularity in response to femoral artery ligation. Our results indicate that STC-1 can affect calcium homeostasis, bone and muscle mass and structure, and angiogenesis through effects on osteoblasts, osteoclasts, myoblasts/myocytes, and endothelial cells.


Subject(s)
Bone and Bones/anatomy & histology , Bone and Bones/physiology , Glycoproteins/physiology , Hormones/physiology , Muscle, Skeletal/anatomy & histology , Muscle, Skeletal/physiology , Animals , Body Composition , Body Constitution , Bone Density , Bone Development , Bone Matrix/metabolism , Calcification, Physiologic , Calcium/blood , Cartilage/metabolism , Female , Gene Expression , Glycoproteins/genetics , Growth/genetics , Growth Plate/anatomy & histology , Hormones/genetics , Male , Mice , Mice, Transgenic , Microscopy, Electron , Neovascularization, Physiologic , Osteoclasts/physiology , Skull/diagnostic imaging , Tomography, X-Ray Computed
2.
Am J Pathol ; 160(6): 2295-307, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12057932

ABSTRACT

Most mouse models of hepatocellular carcinoma have expressed growth factors and oncogenes under the control of a liver-specific promoter. In contrast, we describe here the formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle. FGF19 transgenic mice had elevated hepatic alpha-fetoprotein mRNA as early as 2 months of age, and hepatocellular carcinomas were evident by 10 months of age. Increased proliferation of pericentral hepatocytes was demonstrated by 5-bromo-2'-deoxyuridine incorporation in the FGF19 transgenic mice before tumor formation and in nontransgenic mice injected with recombinant FGF19 protein. Areas of small cell dysplasia were initially evident pericentrally, and dysplastic/neoplastic foci throughout the hepatic lobule were glutamine synthetase-positive, suggestive of a pericentral origin. Consistent with chronic activation of the Wingless/Wnt pathway, 44% of the hepatocellular tumors from FGF19 transgenic mice had nuclear staining for beta-catenin. Sequencing of the tumor DNA encoding beta-catenin revealed point mutations that resulted in amino acid substitutions. These findings suggest a previously unknown role for FGF19 in hepatocellular carcinomas.


Subject(s)
Disease Models, Animal , Fibroblast Growth Factors/biosynthesis , Liver Neoplasms, Experimental/pathology , Muscle, Skeletal/metabolism , Trans-Activators , Zebrafish Proteins , Amino Acid Sequence , Amino Acid Substitution , Animals , Bromodeoxyuridine/metabolism , Cell Division/drug effects , Cytoskeletal Proteins/chemistry , Cytoskeletal Proteins/metabolism , DNA, Neoplasm/chemistry , Enzyme-Linked Immunosorbent Assay , Fibroblast Growth Factors/genetics , Humans , Immunohistochemistry , Liver/metabolism , Liver Neoplasms, Experimental/genetics , Mice , Mice, Transgenic , Molecular Sequence Data , Mutation , Proto-Oncogene Proteins/metabolism , Receptor, Fibroblast Growth Factor, Type 4 , Receptors, Fibroblast Growth Factor/biosynthesis , Recombinant Proteins/metabolism , Wnt Proteins , beta Catenin
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