Nature Genetics
37, 945 - 952 (2005)
Published online: 31 July 2005; | doi:10.1038/ng1614
Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formationXiaofeng Li1, 8, Peng Liu1, 8, Wenzhong Liu1, Peter Maye1, Jianghong Zhang2, Yazhou Zhang1, Marja Hurley3, Caiying Guo1, Adele Boskey4, Le Sun5, Stephen E Harris6, David W Rowe1, Hua Zhu Ke7
& Dianqing Wu11
Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, Connecticut 06030, USA. 2
Department of Oral Biology, University of Missouri at Kansas City, School of Dentistry, Kansas City, Missouri 64108, USA. 3
Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, Connecticut 06030, USA. 4
Hospital for Special Surgery, New York, New York, USA. 5
Welson Pharmaceuticals, Beijing, China. 6
Department of Periodontics and Cellular Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. 7
Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA. 8
These authors contributed equally to this work.
Correspondence should be addressed to Dianqing Wu dwu@neuron.uchc.edu Human and mouse genetic and in vitro evidence has shown that canonical Wnt signaling promotes bone formation, but we found that mice lacking the canonical Wnt antagonist Dickkopf2 (Dkk2) were osteopenic. We reaffirmed the finding that canonical Wnt signaling stimulates osteogenesis, including the differentiation from preosteoblasts to osteoblasts, in cultured osteoblast differentiation models, but we also found that canonical Wnts upregulated the expression of Dkk2 in osteoblasts. Although exogenous overexpression of Dkk before the expression of endogenous canonical Wnt (Wnt7b) suppressed osteogenesis in cultures, its expression after peak Wnt7b expression induced a phenotype resembling terminal osteoblast differentiation leading to mineralization. In addition, osteoblasts from Dkk2-null mice were poorly mineralized upon osteogenic induction in cultures, and Dkk2 deficiency led to attenuation of the expression of osteogenic markers, which could be partially reversed by exogenous expression of Dkk2. Taken together with the finding that Dkk2-null mice have increased numbers of osteoids, these data indicate that Dkk2 has a role in late stages of osteoblast differentiation into mineralized matrices. Because expression of another Wnt antagonist, FRP3, differs from Dkk2 expression in rescuing Dkk2 deficiency and regulating osteoblast differentiation, the effects of Dkk2 on terminal osteoblast differentiation may not be entirely mediated by its Wnt signaling antagonistic activity.
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