How Wnt signaling affects bone repair by mesenchymal stem cells from the bone marrow

Author(s)

Carl A. Gregory
William G. Gunn
Edmigdio Reyes
Angela J. Smolarz
James R. Munoz, Nova Southeastern UniversityFollow
Jeffrey L. Spees
Darwin J. Prockop

Document Type

Article

Publication Date

5-2005

Publication Title

Annals of the New York Academy of Sciences

Volume

1049

Issue/Number

1

First Page

97

ISSN

1749-6632

Last Page

106

Abstract/Excerpt

Human mesenchymal stem cells (hMSCs) from bone marrow are a source of osteoblast progenitors in vivo, and under appropriate conditions they differentiate into osteoblasts ex vivo. The cells provide a convenient cell culture model for the study of osteogenic tissue repair in an experimentally accessible system. Recent advances in the field of skeletal development and osteogenesis have demonstrated that signaling through the canonical wingless (Wnt) pathway is critical for the differentiation of progenitor cell lines into osteoblasts. Inhibition of such signals can predispose hMSCs to cell cycle entry and prevent osteogenesis. Our investigation of the role of Wnt signaling in osteogenesis by hMSCs ex vivo has demonstrated that osteogenesis proceeds in response to bone morphogenic protein 2 stimulation and is sustained by Wnt signaling. In the presence of Dkk-1, an inhibitor of Wnt signaling, the cascade is disrupted, resulting in inhibition of osteogenesis. Peptide mapping studies have provided peptide Dkk-1 agonists and the opportunity for the production of blocking antibodies. Anti-Dkk-1 strategies are clinically relevant since high serum levels of Dkk-1 are thought to contribute to osteolytic lesion formation in multiple myeloma and possibly some forms of osteosarcoma. Specific inhibitors of glycogen synthetase kinase 3beta (GSK3beta), which mimic Wnt signaling, may also have a therapeutic benefit by enhancing in vitro osteogenesis despite the presence of Dkk-1. Antibodies that block Dkk-1 and GSK3beta inhibitors may provide novel opportunities for the enhancement of bone repair in a variety of human diseases such as multiple myeloma and osteosarcoma.

DOI

10.1196/annals.1334.010

NSUWorks Citation

Gregory, C. A., Gunn, W. G., Reyes, E., Smolarz, A. J., Munoz, J. R., Spees, J. L., Prockop, D. J. (2005). How Wnt signaling affects bone repair by mesenchymal stem cells from the bone marrow. Annals of the New York Academy of Sciences, 1049(1), 97-106.
Available at: https://nsuworks.nova.edu/cps_facarticles/1152