Osteoporosis
The Emerging Role of Dickkopf-1 in Bone Biology: Is It the Main Switch Controlling Bone and Joint Remodeling?

https://doi.org/10.1016/j.semarthrit.2011.01.006Get rights and content

Background

Dickkopf-1 (DKK-1), an inhibitor of the Wnt pathway, has recently emerged as an important player in several critical aspects of bone biology.

Methods

We performed an extensive internet search (MEDLINE) using the key words Dickkopf-1 and the abbreviation DKK-1.

Results

DKK-1 is a regulator of bone mass with increased expression linked to osteopenia and decreased expression to high bone mass. Moreover, it appears to actively participate in joint remodeling in animal models of arthritis, with increased levels related to bone resorption and decreased levels to new bone formation. Recent studies indicate its possible involvement in the remodeling process of human systemic rheumatic diseases such as rheumatoid arthritis and ankylosing spondylitis. DKK-1 may also play a role in osteoarthritis, metabolic bone disease (osteoporosis and Paget's disease), as well as multiple myeloma-associated bone disease and prostate cancer bone metastases.

Conclusions

DKK-1 is a regulator of bone mass and joint remodeling. It may be a promising therapeutic target in osteoporosis; monoclonal antibody-based inhibition of Dkk-1 is already under development for osteoporosis treatment. Its role as a regulator of joint remodeling in animal models requires further exploration in humans.

Section snippets

Methods

We performed an extensive internet search (Medline) using the keywords Dickkopf-1 and the abbreviation DKK-1. The computerized search was supplemented by a manual one on the reference lists of the retrieved articles. A total of 248 articles were evaluated; selection was based on relevance to study subject.

Short Overview of the Wnt/β-Catenin Pathway

The Wnt proteins are a family of 19, so far, secreted growth factors that regulate key cellular functions (10). They are capable of binding to a coreceptor complex located at the cell surface, which consists of the low-density lipoprotein receptor-related proteins 5 or 6 (LRP5, LRP6), and a member of the frizzled (Fz) family of proteins. The activation of the pathway is tightly linked to cytoplasmic β-catenin levels and is shown in Figure 1.

The Wnt pathway is tightly regulated at multiple

Discussion

The discovery of DKK-1, a soluble inhibitor of the Wnt pathway, enhanced our understanding of bone physiology and its disturbances in pathologic conditions such as osteoporosis, joint remodeling in inflammatory arthritides, osteoarthritis, and malignant bone disease and opened new avenues toward more effective therapies. Evidence suggests that targeting DKK-1 may be a therapeutic approach in osteoporosis. DKK-1 inhibitors emerge as promising tools to enhance Wnt signaling and stimulate new bone

Conclusions

The role of DKK-1 in joint remodeling and bone mass regulation warrants further exploration, especially in humans, where data are scarce. It appears as an interesting target for the treatment of osteoporosis; moreover, inhibiting or enhancing the function of DKK-1 may be a way of altering the process of joint remodeling where needed. For example, mAb-based inhibition of DKK-1 may attenuate erosive disease and serve as an adjunct therapy in RA. On the other hand, enhancing/restoring the function

References (53)

  • I.R. Reid et al.

    Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial

    Am J Med

    (1996)
  • M.J. Marshall et al.

    Increased circulating Dickkopf-1 in Paget's disease of bone

    Clin Biochem

    (2009)
  • S. Yaccoby et al.

    Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo

    Blood

    (2007)
  • L. Bubendorf et al.

    Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients

    Hum Pathol

    (2000)
  • R. Karim et al.

    The significance of the Wnt pathway in the pathology of human cancers

    Pathology

    (2004)
  • Y. Kawano et al.

    Secreted antagonists of the Wnt signalling pathway

    J Cell Sci

    (2003)
  • M.L. Johnson et al.

    The Wnt signaling pathway and bone metabolism

    Curr Opin Rheumatol

    (2007)
  • V. Krishnan et al.

    Regulation of bone mass by Wnt signaling

    J Clin Invest

    (2006)
  • J.R. Miller

    The Wnts

    Genome Biol

    (2002)
  • S.R. Goldring et al.

    Eating bone or adding it: the Wnt pathway decides

    Nat Med

    (2007)
  • L.M. Boyden et al.

    High bone density due to a mutation in LDL-receptor-related protein 5

    N Engl J Med

    (2002)
  • D. Diarra et al.

    Dickkopf-1 is a master regulator of joint remodeling

    Nat Med

    (2007)
  • R. Baron et al.

    Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton

    Endocrinology

    (2007)
  • F. Morvan et al.

    Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass

    J Bone Miner Res

    (2006)
  • G.R. Heiland et al.

    Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression

    Ann Rheum Dis

    (2010)
  • W. Mak et al.

    Biphasic glucocorticoid-dependent regulation of Wnt expression and its inhibitors in mature osteoblastic cells

    Calcif Tissue Int

    (2009)
  • Cited by (88)

    • Dickkopf-1 as a promising therapeutic target for autoimmune diseases

      2022, Clinical Immunology
      Citation Excerpt :

      The Wnt signaling pathway takes an important part in embryogenesis, organogenesis and homeostasis [13,14]. By promoting osteoblastogenesis, the Wnt/β-catenin pathway signaling may cause new bone formation [16–21]. Also, the canonical Wnt/β-catenin pathway has been identified to play a crucial role in skeletal development and homeostasis in adults, and dysregulation of this signaling is associated with bone pathology [15].

    View all citing articles on Scopus

    The authors have no conflicts of interest to disclose.

    View full text