The role of Dickkopf-1 in bone development, homeostasis, and disease

Abstract

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.

Figure 1

The presence of certain Wnt proteins activates “canonical signaling” by binding to FZD and low-density LRP5 and LRP6 coreceptors causing Dvl to attract proteins away from the β-catenin destruction complex thereby preventing β-catenin from being degraded. If not degraded, β-catenin is stabilized and translocates to the nucleus where it binds to the transcription factor TCF4 and enhances target gene expression, including cyclin D1, c-myc, c-jun, vascular endothelial growth factor (VEGF), and several others that are associated with enhanced cell growth. In the presence of DKK1, which competitively binds to LRP5/6 causing it to bind to Kremen and become inactive, GSK3β, Axin, APC, and CKIα form a β-catenin destruction complex. CKIα and GSK3β phosphorylate β-catenin causing it to be recognized by β-transducin repeat protein, ubiquitinated, and degraded by proteasomes, thereby inhibiting “canonical signaling.”

Figure 2

The prevailing model of the role of DKK1 and the mesenchymal cell lineage in bone development and bone mass homeostasis. Wnt 3a, 5a, and 7b and Ihh cooperatively promote osteoblast differentiation, whereas DKK1 inhibits osteoblastogenesis and shifts the developmental program toward adipogenesis. β-catenin/TCF1 promotes early osteoblast lineage commitment through induction of the master bone development protein Runx2. Runx2 then promotes transcriptional activation of a second master bone development transcription factor Osterix (Osx), which uses DKK1 to repress Runx2 expression to further promote osteoblast progenitor maturation. Finally, phenotypic lineage-specific markers for osteoblast maturation are illustrated.^,

Figure 3

DKK1 is both anabolic and anticatabolic in bone. TNF-α enhances DKK1 secretion which inhibits MSC-derived osteoblastogenesis and lowers OPG levels, resulting in reduced bone accretion. In addition, DKK1 enhances RANKL levels, and the increased RANKL:OPG ratio activates osteoclast activity, leading to bone resorption.

Figure 4

Metastatic cancer cells that secrete elevated levels of DKK1 disrupt the balance of osteoblastogenesis and osteoclastogenesis in favor of an osteolytic microenvironment that is conducive to tumor growth. MM has a unique and absolute requirement for the bone marrow microenvironment for its growth and survival and MM plasma cells may cultivate this “soil” by synthesizing and secreting DKK1. The primary effect of DKK1 appears to be the disruption of the differention of MSC in the osteoblasts (OB). RANK signaling regulates osteoclast development and Wnt signaling in MSC/OB differentially regulates RANKL and OPG, a RANKL decoy, which together modulate osteoclast development. DKK1 suppression of Wnt in MSC/OB leads to increased production of RANKL and IL-6 and decreased production of OPG. The shift in RANKL:OPG ratios leads to increased osteoclastogenesis and IL-6 is a potent survival factor of MM cells. The subsequent loss of osteoblasts and increase in osteoclasts causes lytic bone destruction, hypercalcemia, and loss of normal bone marrow function. A vicious cycle of bone destruction and tumor growth ensues. The absence of DKK1 in a subset of MM suggests that other soluble factors produced by MM cells may contribute to this process. These include MIP1a, sFRP-2, IL-3, RANKL, and possibly sFRP-3 (see “Proposed model of DKK1-mediated promotion of bone metastases” for more details).