Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF. Mol Cancer 2007 Oct 30;6:71
Date
11/01/2007Pubmed ID
17971207Pubmed Central ID
PMC2173906DOI
10.1186/1476-4598-6-71Scopus ID
2-s2.0-37749040562 (requires institutional sign-in at Scopus site) 158 CitationsAbstract
BACKGROUND: 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.
METHODS: We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation.
RESULTS: 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.
CONCLUSION: 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.
Author List
Fujita K, Janz SAuthor
Siegfried Janz MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Morphogenetic Protein 2
Bone Morphogenetic Proteins
Cell Differentiation
Gene Expression Regulation, Neoplastic
Intercellular Signaling Peptides and Proteins
Macrophage Colony-Stimulating Factor
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Models, Biological
Neoplasm Transplantation
Osteoblasts
Osteoprotegerin
Plasmacytoma
RANK Ligand
Signal Transduction
Transforming Growth Factor beta
Tumor Suppressor Protein p53
Wnt Proteins
