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Blood, 15 January 2009, Vol. 113, No. 3, pp. 517-525.
Prepublished online as a Blood First Edition Paper on October 3, 2008August 7, 2008; DOI 10.1182/blood-2008-03-145169.
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Submitted March 24, 2008
Accepted July 25, 2008
The role of Dickkopf-1 in bone development, homeostasis and disease
Joseph J. Pinzone, Brett M. Hall, Nanda K. Thudi, Martin Vonau, Ya-Wei Qiang, Thomas J. Rosol, and John D. Shaughnessy Jr.*
Department of Internal Medicine, The Ohio State University, Columbus, OH, United States
Department of Pediatrics, The Ohio State University, Columbus, OH, United States
Department of Veterinary Sciences, The Ohio State University, Columbus, OH, United States
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, United States
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
* Corresponding author; email: shaughnessyjohn{at}uams.edu.
Wnt/ -catenin signaling is central to bone development and homeostasis in adulthood and its deregulation is associated with bone pathologies. Dickkopf-1 (DKK1), is a soluble inhibitor of Wnt/-catenin signaling required for embryonic head development. DKK1 regulates Wnt signaling by binding to the Wnt co-receptor LRP5/Arrow. LRP5 mutations causing high bone mass syndromes disrupt DKK1-mediated regulation of LRP5. Forced overexpression of Dkk1 in osteoblasts causes osteopenia, disruption of the hematopoietic stem cell (HSC) niche, and defects in HSC function. Dkk1 also inhibits fracture repair. Studies suggest that DKK1 activation in osteoblasts is the underlying cause of glucocorticoid- and estrogen deficiency-mediated osteoporosis, and at least partially underlies the teratogenic effects of thalidomide on limb development. DKK1 induces proliferation of mesenchymal stem cells (MSC) in-vitro and may play a role in the development of high-grade undifferentiated pleomorphic sarcomas derived from MSC and osteosarcomas. DKK1 has been implicated in causing erosive arthritis, the osteolytic phenotypes of multiple myeloma and metastatic breast cancer, and oteoblastic metastases of prostate cancer. Preclinical studies have shown that neutralizing DKK1/Dkk1 and/or enhancing Wnt/-catenin signaling may prove effective in treating bone pathologies. Here we review the rapidly growing body of literature defining a pivotal role for DKK1 in bone health and disease.
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