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

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.

[1]  Michael L. Wang,et al.  Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma. , 2007, Blood.

[2]  Janet L Stein,et al.  Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression* , 2005, Journal of Biological Chemistry.

[3]  J. Rodríguez-León,et al.  A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. , 2004, Developmental biology.

[4]  Yan Li,et al.  LDL-receptor-related protein 6 is a receptor for Dickkopf proteins , 2001, Nature.

[5]  F. Zhan,et al.  The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. , 2003, The New England journal of medicine.

[6]  U. Rüther,et al.  The Wnt antagonist Dickkopf‐1 is regulated by Bmp signaling and c‐Jun and modulates programmed cell death , 2002, The EMBO journal.

[7]  Ivan Lobov,et al.  Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor , 2002, The Journal of cell biology.

[8]  D. Esseltine,et al.  Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma , 2005, British journal of haematology.

[9]  C. Edwards.  Wnt signaling: bone's defense against myeloma. , 2008, Blood.

[10]  G. Boland,et al.  Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells , 2004, Journal of cellular biochemistry.

[11]  Terry M Therneau,et al.  A long-term study of prognosis in monoclonal gammopathy of undetermined significance. , 2002, The New England journal of medicine.

[12]  G. Karsenty,et al.  In vivo analysis of Wnt signaling in bone. , 2007, Endocrinology.

[13]  Bart O. Williams,et al.  Essential Role of β-Catenin in Postnatal Bone Acquisition* , 2005, Journal of Biological Chemistry.

[14]  Bart Barlogie,et al.  A phase 2 study of bortezomib in relapsed, refractory myeloma. , 2003, The New England journal of medicine.

[15]  Terry M Therneau,et al.  Prevalence of monoclonal gammopathy of undetermined significance. , 2006, The New England journal of medicine.

[16]  B. Barlogie,et al.  Dkk1-induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma. , 2008, Bone.

[17]  DIMITRIOS J. HADJIDAKIS,et al.  Bone Remodeling , 2006, Annals of the New York Academy of Sciences.

[18]  Hans Clevers,et al.  Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. , 2005, Developmental cell.

[19]  T. Rosol,et al.  Zoledronic acid decreased osteolysis but not bone metastasis in a nude mouse model of canine prostate cancer with mixed bone lesions , 2008, The Prostate.

[20]  T. Kishimoto.  Interleukin-6: from basic science to medicine--40 years in immunology. , 2005, Annual review of immunology.

[21]  J. Shaughnessy,et al.  Thalidomide induces limb deformities by perturbing the Bmp/Dkkl/Wnt signaling pathway , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  Nicola Baldini,et al.  Paracrine inhibition of osteoblast differentiation induced by neuroblastoma cells , 2008, International journal of cancer.

[23]  M. Krinks,et al.  Frzb-1, an antagonist of Wnt-1 and Wnt-8, does not block signaling by Wnts -3A, -5A, or -11. , 1997, Biochemical and biophysical research communications.

[24]  R. Baron,et al.  Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. , 2007, Endocrinology.

[25]  Kenneth C. Anderson,et al.  Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets , 2007, Nature Reviews Cancer.

[26]  D. Prockop,et al.  The Wnt Signaling Inhibitor Dickkopf-1 Is Required for Reentry into the Cell Cycle of Human Adult Stem Cells from Bone Marrow* , 2003, Journal of Biological Chemistry.

[27]  Hypomorphic expression of Dkk1 in the doubleridge mouse: dose dependence and compensatory interactions with Lrp6 , 2004, Development.

[28]  R. Baron,et al.  Deletion of a Single Allele of the Dkk1 Gene Leads to an Increase in Bone Formation and Bone Mass , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  Xi He,et al.  SOST Is a Ligand for LRP5/LRP6 and a Wnt Signaling Inhibitor* , 2005, Journal of Biological Chemistry.

[30]  S. Colla,et al.  Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. , 2004, Blood.

[31]  B. Alman,et al.  Beta-Catenin Signaling Plays a Disparate Role in Different Phases of Fracture Repair: Implications for Therapy to Improve Bone Healing , 2007, PLoS medicine.

[32]  J. Nathans,et al.  A new secreted protein that binds to Wnt proteins and inhibits their activites , 1999, Nature.

[33]  M. Bouxsein,et al.  Essential role of beta-catenin in postnatal bone acquisition. , 2005, The Journal of biological chemistry.

[34]  E. Schwarz,et al.  Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. , 2006, Gene.

[35]  M. Peters,et al.  Serum concentrations of DKK‐1 correlate with the extent of bone disease in patients with multiple myeloma , 2008, European journal of haematology.

[36]  P. Genever,et al.  Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro , 2006, Journal of Cell Science.

[37]  C. Niehrs,et al.  Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction , 1998, Nature.

[38]  S. Goldstein,et al.  Bone mass is inversely proportional to Dkk1 levels in mice. , 2007, Bone.

[39]  N. Munshi,et al.  Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. , 2007, Blood.

[40]  B. Alman,et al.  β-Catenin Signaling Pathway Is Crucial for Bone Morphogenetic Protein 2 to Induce New Bone Formation* , 2007, Journal of Biological Chemistry.

[41]  O. Stephens,et al.  Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. , 2007, Molecular endocrinology.

[42]  O. MacDougald,et al.  Role of wnts in prostate cancer bone metastases , 2006, Journal of cellular biochemistry.

[43]  P. Jourdon,et al.  Concise Review: Embryonic Stem Cells: A New Tool to Study Osteoblast and Osteoclast Differentiation , 2007, Stem cells.

[44]  Feng-Sheng Wang,et al.  Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats. , 2007, Bone.

[45]  S. Aaronson,et al.  Prostate cancer cells promote osteoblastic bone metastases through Wnts. , 2005, Cancer research.

[46]  O. Stephens,et al.  Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. , 2008, Blood.

[47]  L. Hofbauer,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.

[48]  R. Baron,et al.  Christof Niehrs Kremen Induces Limb Defects and High Targeted Disruption of the Wnt Regulator Supplemental Material , 2008 .

[49]  Minrong Ai,et al.  Reduced Affinity to and Inhibition by DKK1 Form a Common Mechanism by Which High Bone Mass-Associated Missense Mutations in LRP5 Affect Canonical Wnt Signaling , 2005, Molecular and Cellular Biology.

[50]  V. Rizzoli,et al.  Myeloma cells and bone marrow osteoblast interactions: Role in the development of osteolytic lesions in multiple myeloma , 2007, Leukemia & lymphoma.

[51]  G. Mundy,et al.  Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease , 2007, British journal of haematology.

[52]  T. Yoneda,et al.  Breast cancer‐derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone metastases , 2008, International journal of cancer.

[53]  Xizhi Guo,et al.  Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. , 2005, Developmental cell.

[54]  J. A. Robinson,et al.  High Bone Mass in Mice Expressing a Mutant LRP5 Gene , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[55]  Changshan Wu,et al.  The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. , 2002, Developmental biology.

[56]  D. Prockop,et al.  A Crosstalk Between Myeloma Cells and Marrow Stromal Cells Stimulates Production of DKK1 and Interleukin‐6: A Potential Role in the Development of Lytic Bone Disease and Tumor Progression in Multiple Myeloma , 2006, Stem cells.

[57]  Minrong Ai,et al.  The Binding Between Sclerostin and LRP5 is Altered by DKK1 and by High-Bone Mass LRP5 Mutations , 2008, Calcified Tissue International.

[58]  T. Michiue,et al.  Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling. , 2008, Developmental cell.

[59]  J. Chirgwin,et al.  A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[60]  F. Hamdy,et al.  Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases. , 2007, The American journal of pathology.

[61]  A. Abo,et al.  R-Spondin family members regulate the Wnt pathway by a common mechanism. , 2008, Molecular biology of the cell.

[62]  Miikka Vikkula,et al.  LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development , 2001, Cell.

[63]  F. Luyten,et al.  Primary Structure and Tissue Distribution of FRZB, a Novel Protein Related to Drosophila Frizzled, Suggest a Role in Skeletal Morphogenesis* , 1996, The Journal of Biological Chemistry.

[64]  Christof Niehrs,et al.  Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. , 2002, Nature.

[65]  R. Fonseca,et al.  Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma , 2007, Leukemia.

[66]  R. Shah,et al.  Dickkopf‐1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis , 2008, The Prostate.

[67]  Y. Miyagi,et al.  Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. , 2007, Cancer research.

[68]  Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth. , 2008, Blood.

[69]  G. Mundy,et al.  Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. , 2008, Blood.

[70]  Hongwei Xu,et al.  The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells. , 2007, Blood.

[71]  Richard P Lifton,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.

[72]  D. Ornitz,et al.  Sequential roles of Hedgehog and Wnt signaling in osteoblast development , 2004, Development.

[73]  S. Kwan Tat,et al.  IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. , 2004, Cytokine & growth factor reviews.

[74]  H. Clevers.  Wnt/beta-catenin signaling in development and disease. , 2006, Cell.

[75]  J. I. Izpisúa Belmonte,et al.  Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. , 2001, Developmental cell.

[76]  A. Muñoz,et al.  The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer , 2005, Oncogene.

[77]  S. Turcotte,et al.  The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types , 2007, British Journal of Cancer.

[78]  D. Heath,et al.  Expression Profiling and Functional Analysis of Wnt Signaling Mechanisms in Mesenchymal Stem Cells , 2004, Stem cells.

[79]  D. Galas,et al.  Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. , 2001, American journal of human genetics.

[80]  Wei Huang,et al.  Signaling and transcriptional regulation in osteoblast commitment and differentiation. , 2007, Frontiers in bioscience : a journal and virtual library.

[81]  Feng-Sheng Wang,et al.  Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss. , 2008, Endocrinology.

[82]  Christof Niehrs,et al.  Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling , 2002, Nature.

[83]  N. Socci,et al.  Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway. , 2007, The Journal of clinical investigation.

[84]  D. Scadden,et al.  The hematopoietic stem cell in its place , 2006, Nature Immunology.

[85]  A. Bosserhoff,et al.  Expression of Dickkopf genes is strongly reduced in malignant melanoma , 2006, Oncogene.

[86]  Mark L. Johnson,et al.  A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. , 2002, American journal of human genetics.

[87]  D. Scadden,et al.  Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. , 2008, Cell stem cell.

[88]  F. Journé,et al.  Increased Dickkopf-1 expression in breast cancer bone metastases , 2007, British Journal of Cancer.

[89]  C. Crews,et al.  Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. , 2003, The Journal of clinical investigation.

[90]  Xi He,et al.  LRP5 Mutations Linked to High Bone Mass Diseases Cause Reduced LRP5 Binding and Inhibition by SOST* , 2006, Journal of Biological Chemistry.

[91]  Bart Barlogie,et al.  Interpreting the molecular biology and clinical behavior of multiple myeloma in the context of global gene expression profiling , 2003, Immunological reviews.

[92]  Georg Schett,et al.  Dickkopf-1 is a master regulator of joint remodeling , 2007, Nature Medicine.

[93]  Rocky S Tuan,et al.  Canonical and non‐canonical wnts differentially affect the development potential of primary isolate of human bone marrow mesenchymal stem cells , 2007, Journal of cellular physiology.

[94]  S. O’Rahilly,et al.  The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis , 2006, Journal of Cell Science.

[95]  Alison Rowe,et al.  Wise, a context-dependent activator and inhibitor of Wnt signalling , 2003, Development.

[96]  Bart Barlogie,et al.  Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. , 2007, Blood.

[97]  R. Kutner,et al.  A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies , 2007, British Journal of Cancer.

[98]  M. Bouxsein,et al.  Decreased BMD and Limb Deformities in Mice Carrying Mutations in Both Lrp5 and Lrp6 , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[99]  Oscar L. Sierra,et al.  Msx2 Exerts Bone Anabolism via Canonical Wnt Signaling* , 2008, Journal of Biological Chemistry.

[100]  G. Boland,et al.  Cross‐talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation , 2007, Journal of cellular biochemistry.