Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation

Gregory A. Clines, Khalid Mohammad, Yongde Bao, Owen W. Stephens, Larry J. Suva, John D. Shaughnessy, Jay W. Fox, John Chirgwin, Theresa Guise

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

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 β-A, serum/glucocorticoid regulated kinase, receptor activator of nuclear factor κB 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 β-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.

Original languageEnglish (US)
Pages (from-to)486-498
Number of pages13
JournalMolecular Endocrinology
Volume21
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

Fingerprint

Endothelin-1
Osteogenesis
Osteoblasts
Wnt Signaling Pathway
Organ Culture Techniques
Bone and Bones
Cysteine-Rich Protein 61
Tissue Inhibitor of Metalloproteinase-3
Interleukin-11
Neoplasm Metastasis
Connective Tissue Growth Factor
Catenins
Snails
Microarray Analysis
Cytoplasmic and Nuclear Receptors
Conditioned Culture Medium
Neutralizing Antibodies
Multiple Myeloma
Real-Time Polymerase Chain Reaction
Interleukin-6

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. / Clines, Gregory A.; Mohammad, Khalid; Bao, Yongde; Stephens, Owen W.; Suva, Larry J.; Shaughnessy, John D.; Fox, Jay W.; Chirgwin, John; Guise, Theresa.

In: Molecular Endocrinology, Vol. 21, No. 2, 02.2007, p. 486-498.

Research output: Contribution to journalArticle

Clines, Gregory A. ; Mohammad, Khalid ; Bao, Yongde ; Stephens, Owen W. ; Suva, Larry J. ; Shaughnessy, John D. ; Fox, Jay W. ; Chirgwin, John ; Guise, Theresa. / Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 2. pp. 486-498.
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