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Stanniocalcin 1 Alters Muscle and Bone Structure and Function in Transgenic Mice

Departments of Molecular Oncology (E.H.F., M.B.), Pathology (S.G., D.M.F.), Physiology (C.Z., G.I., H.S., J.H., S.B., J.R., R.A.D.C., L.P.-B., M.E.G.), and Safety Assessment (R.E.), Genentech Inc., South San Francisco, California 94080; and Department of Physiology (G.F.W.), Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada

Address all correspondence and requests for reprints to: Dr. Ellen Filvaroff, Department of Molecular Oncology, Genentech, Inc., MS 72B, 1 DNA Way, South San Francisco, California 94080. E-mail: filvarof{at}gene.com.

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.

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