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Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation

Nature Genetics volume 37, pages 945–952 (2005)Cite this article

Abstract

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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Figure 1: Dkk2-null mice are osteopenic.
Figure 2: Osteoblasts derived from Dkk2-null mice show poor mineralization in cultures.
Figure 3: Canonical Wnts stimulate osteogenesis and osteoblast differentiation.
Figure 4: Dkk expression during osteoblast differentiation.
Figure 5: Expression of osteogenic markers Wnt7b, Dkk1 and Dkk2 in differentiating osteoblasts.
Figure 6: Dkk2 stimulates mineralization.
Figure 7: Effects of Dkk2 deficiency on osteoclast activity, and a model for the involvement of Wnt and Dkk in the regulation of osteogenesis.

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Acknowledgements

We thank the University of Connecticut Health Center transgenic facility for generating Dkk2-null mice, C. Niehrs for cDNAs and T. Crawford and H. Simmons for technical support for bone densitometry and histomorphometry. The work is supported by grants from the US National Institutes of Health (to D.W., D.W.R., M.H. and S.E.H.)

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Author notes

  1. Xiaofeng Li and Peng Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, 06030, Connecticut, USA

    Xiaofeng Li, Peng Liu, Wenzhong Liu, Peter Maye, Yazhou Zhang, Caiying Guo, David W Rowe & Dianqing Wu

  2. Department of Oral Biology, University of Missouri at Kansas City, School of Dentistry, Kansas City, 64108, Missouri, USA

    Jianghong Zhang

  3. Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, 06030, Connecticut, USA

    Marja Hurley

  4. Hospital for Special Surgery, New York, New York, USA

    Adele Boskey

  5. Welson Pharmaceuticals, Beijing, China

    Le Sun

  6. Department of Periodontics and Cellular Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, 78229, Texas, USA

    Stephen E Harris

  7. Pfizer Global Research and Development, Groton Laboratories, Groton, 06340, Connecticut, USA

    Hua Zhu Ke

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Correspondence to Dianqing Wu.

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Competing interests

This study was supported financially by Enzo Biochem and Pfizer. X.L. is an employee of Enzo Biochem. H.Z.K. is an employee of Pfizer.

Supplementary information

Supplementary Fig. 1

Serum bone AP, calcium, phosphorus, and CO AP levels. (PDF 11 kb)

Supplementary Fig. 2

Osteogenesis of calvarial osteoblasts. (PDF 64 kb)

Supplementary Fig. 3

Expression of LRP5 and LRP6 during BMSO differentiation. (PDF 64 kb)

Supplementary Fig. 4

Proliferation, apoptosis and LRP expression in osteoblasts. (PDF 10 kb)

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Li, X., Liu, P., Liu, W. et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 37, 945–952 (2005). https://doi.org/10.1038/ng1614

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