Wnt/beta-catenin signaling is central to bone development and homeostasis in 
adulthood and its deregulation is associated with bone pathologies. Dickkopf-1 
(DKK1), a soluble inhibitor of Wnt/beta-catenin signaling required for embryonic 
head development, regulates Wnt signaling by binding to the Wnt coreceptor 
lipoprotein-related protein-5 (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 osteoblastic metastases of prostate 
cancer. Preclinical studies have shown that neutralizing DKK1/Dkk1 and/or 
enhancing Wnt/beta-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.