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a Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut, USA b The University of Connecticut School of Medicine, Farmington, Connecticut, USA
Key Words: bone morphogenetic proteins • (BMP) • BMP antagonists • CCN proteins • nephroblastoma overexpressed • notch • osteoblastogenesis • Wnt
Address for correspondence: Ernesto Canalis, M.D., Department of Research, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, CT 06105-1299. Voice: 860-714-4068; fax: 860-714-8053. ecanalis{at}stfranciscare.org
Nephroblastoma overexpressed (Nov), a member of the CCN family of proteins, is expressed by osteoblasts and its transcription is regulated by transforming growth factor (TGF)-β and bone morphogenetic proteins (BMP). CCN proteins can interact with TGF-β, BMPs, and Wnt. We explored the function of Nov in skeletal cells, in vitro and in vivo. Constitutive overexpression of Nov in cells of the osteoblastic lineage impaired osteoblastic differentiation, opposed the biological effects of BMP-2 and Wnt 3 and impaired BMP-2 and Wnt signaling, indicating that Nov has BMP-2 antagonistic activity. Transgenic mice overexpressing Nov under the control of the osteocalcin promoter exhibited osteopenia secondary to decreased bone formation, confirming the effects in vitro. GST pulldown experiments demonstrated direct Nov–BMP interactions. In conclusion, Nov has BMP antagonistic properties and inhibits osteoblastogenesis and osteoblastic function.
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