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Dickkopf Homolog 1 Mediates Endothelin-1-Stimulated New Bone Formation

Department of Internal Medicine, Division of Endocrinology and Metabolism, Aurbach Laboratory (G.A.C., K.S.M., J.M.C, T.A.G.) and the Department of Microbiology and Biomolecular Research Facility (Y.B., J.W.F.), The University of Virginia, Charlottesville, Virginia 22908; and Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy (O.W.S., J.D.S.) and Department of Orthopaedic Surgery, Center for Orthopaedic Research (L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Address all correspondence to: Theresa A. Guise, Division of Endocrinology and Metabolism, The University of Virginia, P.O. Box 801419, Charlottesville, Virginia 22908-1419. E-mail: tag4n{at}virginia.edu. Address reprint requests to: Gregory A. Clines, Division of Endocrinology and Metabolism, The University of Virginia, P.O. Box 801420, Charlottesville, Virginia 22908-1420.

Tumor-produced endothelin-1 (ET-1) stimulates osteoblasts to form new bone and is an important mediator of osteoblastic bone metastasis. The anabolic actions of ET-1 in osteoblasts were investigated by gene microarray analyses of murine neonatal calvarial organ cultures. Targets of ET-1 action were validated by real-time RT-PCR in murine primary osteoblast cultures. IL-6, IL-11, the CCN (CYR61, CTGF, NOV) family members cysteine-rich protein 61 and connective tissue growth factor, inhibin ß-A, serum/glucocorticoid regulated kinase, receptor activator of nuclear factor B ligand, snail homolog 1, tissue inhibitor of metalloproteinase 3, and TG-interacting factor transcripts were increased by ET-1. ET-1 decreased the transcript for the Wnt signaling pathway inhibitor, dickkopf homolog 1 (Dkk1). Calvarial organ cultures treated with ET-1 had lower concentrations of DKK1 protein in conditioned media than control cultures. High DKK1 concentrations in bone marrow suppress bone formation in multiple myeloma. We hypothesized that the converse occurs in osteoblastic bone metastasis, where ET-1 stimulates osteoblast activity by reducing autocrine production of DKK1. Recombinant DKK1 blocked ET-1-mediated osteoblast proliferation and new bone formation in calvarial organ cultures, whereas a DKK1-neutralizing antibody increased osteoblast numbers and new bone formation. ET-1 directed nuclear translocation of ß-catenin in osteoblasts, indicating activation of the Wnt signaling pathway. The data suggest that ET-1 increases osteoblast proliferation and new bone formation by activating the Wnt signaling pathway through suppression of the Wnt pathway inhibitor DKK1.

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