Dickkopf-1 is a master regulator of joint remodeling

Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-α (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodeling.

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

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

[3]  E. Wagner,et al.  HIF-1 mediated upregulation of VEGF and VEGF-R in systemic sclerosis (SSc): Imbalance with angiostatic factors suggests VEGF as a novel option for the treatment of ischemia in patients with SSc , 2002, Annals of the rheumatic diseases.

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

[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]  S. Goldring,et al.  Rheumatic diseases: the effects of inflammation on bone , 2005, Immunological reviews.

[7]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[8]  P. M. van der Kraan,et al.  Adenoviral overexpression of Smad-7 and Smad-6 differentially regulates TGF-beta-mediated chondrocyte proliferation and proteoglycan synthesis. , 2003, Osteoarthritis and cartilage.

[9]  T. Ochiya,et al.  Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  W. B. van den Berg,et al.  Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-beta injections. , 2000, Osteoarthritis and cartilage.

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

[12]  M. Prevoo,et al.  Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. , 1996, Arthritis and rheumatism.

[13]  J. Loureiro,et al.  The Wnts , 1999, Current Biology.

[14]  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.

[15]  M. Dougados,et al.  The influence of peripheral arthritis on disease activity in ankylosing spondylitis patients as measured with the Bath Ankylosing Spondylitis Disease Activity Index. , 2004, Arthritis & Rheumatism.

[16]  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.

[17]  A R Pettit,et al.  TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. , 2001, The American journal of pathology.

[18]  J. J. Bunim,et al.  Primer on the rheumatic diseases. , 1949, Journal of the American Medical Association.

[19]  Hans Clevers,et al.  Negative Feedback Loop of Wnt Signaling through Upregulation of Conductin/Axin2 in Colorectal and Liver Tumors , 2002, Molecular and Cellular Biology.

[20]  M. Feldmann,et al.  Anti-TNF therapy: where have we got to in 2005? , 2005, Journal of autoimmunity.

[21]  H. Bergmeister,et al.  Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction. , 2004, Arthritis and rheumatism.

[22]  M. Peifer,et al.  Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus. , 2000, Science.

[23]  S. Takeshita,et al.  TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. , 2000, The Journal of clinical investigation.

[24]  E. Wagner,et al.  Osteoclasts are essential for TNF-alpha-mediated joint destruction. , 2002, The Journal of clinical investigation.

[25]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[26]  D. Kioussis,et al.  Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. , 1991, The EMBO journal.

[27]  T. Thornhill,et al.  Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. , 1998, The American journal of pathology.

[28]  A. Calin,et al.  A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. , 1994, The Journal of rheumatology.

[29]  A. Cats,et al.  Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. , 1984, Arthritis and rheumatism.

[30]  J. Smolen,et al.  Arthritis Induces Lymphocytic Bone Marrow Inflammation and Endosteal Bone Formation , 2004 .

[31]  G. Firestein.  Evolving concepts of rheumatoid arthritis , 2003, Nature.

[32]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

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

[34]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[35]  H. Bergmeister,et al.  Isolated and combined inhibition of TNF-, IL-1 and RANKL-pathways in TNF-induced arthritis: effects on synovial inflammation, bone erosion and cartilage destruction , 2003, Arthritis Research & Therapy.

[36]  J. O'dell,et al.  Therapeutic strategies for rheumatoid arthritis. , 2004, The New England journal of medicine.

[37]  Stuart A. Aaronson,et al.  Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow , 2001, Nature Cell Biology.

[38]  T. Bringman,et al.  Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors , 1986, Nature.

[39]  W. B. van den Berg,et al.  Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor beta/bone morphogenetic protein inhibitors during experimental osteoarthritis. , 2003, Arthritis and rheumatism.