Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF

Ken-ichi Fujita; Siegfried Janz

doi:10.1186/1476-4598-6-71

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Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF

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Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF

Ken-ichi Fujita and Siegfried Janz

Molecular cancer, Vol.6(1), pp.71-71

10/30/2007

DOI: 10.1186/1476-4598-6-71

PMCID: PMC2173906

PMID: 17971207

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Abstract

Enhanced osteoblast-dependent osteoclastogenesis due to inhibition of Wnt/beta-catenin signaling in bone morphogenic protein (BMP)-driven osteoprogenitors has been repeatedly implicated in the natural history of cancer-associated osteolytic lesions, but the mechanism of this bone loss is poorly understood. We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation. We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/beta-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D3 and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective. Our results suggest that inhibited Wnt/beta-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss.

Neoplasm Transplantation

Tumor Suppressor Protein p53 - biosynthesis

Macrophage Colony-Stimulating Factor - biosynthesis

Signal Transduction

Bone Morphogenetic Protein 2

Osteoprotegerin - biosynthesis

Gene Expression Regulation, Neoplastic

Intercellular Signaling Peptides and Proteins - biosynthesis

RANK Ligand - biosynthesis

Wnt Proteins - metabolism

Mice, Inbred C3H

Plasmacytoma - metabolism

Bone Morphogenetic Proteins - metabolism

Animals

Models, Biological

Cell Differentiation

Mice

Mice, Inbred BALB C

Osteoblasts - metabolism

Transforming Growth Factor beta - metabolism

Details

Title: Subtitle: Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF
Creators: Ken-ichi Fujita - Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. fujitak@mail.nih.gov
Siegfried Janz
Resource Type: Journal article
Publication Details: Molecular cancer, Vol.6(1), pp.71-71
DOI: 10.1186/1476-4598-6-71
PMID: 17971207
PMCID: PMC2173906
NLM abbreviation: Mol Cancer
ISSN: 1476-4598
eISSN: 1476-4598
Grant note: Intramural NIH HHS
Language: English
Date published: 10/30/2007
Academic Unit: Pathology
Record Identifier: 9984083897502771

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