Dickkopf-1 is a master regulator of joint remodeling

Maastricht University, Maestricht, Limburg, Netherlands
Nature Medicine (Impact Factor: 28.05). 03/2007; 13(2):156-63. DOI: 10.1038/nm1538
Source: PubMed

ABSTRACT 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-alpha (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.

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Available from: Marina Stolina, Jul 30, 2015
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    • " unloading of the skeleton, bone growth, bone remodeling, and fracture repair by increasing osteoblast commitment from progenitor cells and by stimulating their proliferation and activation (Agholme and Aspenberg 2011, Kim et al. 2013). In addition , there is crosstalk between the bone anabolic Wnt pathway and the bone-catabolic RANKL/OPG pathway (Diarra et al. ? 7967 2007), with recent studies suggesting that the Wnt pathway is in control of osteoclast differentiation and activation through its actions on the osteoblasts, and by participating in osteoclast recruitment and the initiation of bone remodeling (Bellido 2014). We are not aware of any study investigating the role of the Wnt system in the pathol"
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    ABSTRACT: Background and purpose — Charcot neuropathy is characterized by bone destruction in a foot leading to deformity, instability, and risk of amputation. Little is known about the pathogenic mechanisms. We hypothesized that the bone-regulating Wnt/β-catenin and RANKL/OPG pathways have a role in Charcot arthropathy. Patients and methods — 24 consecutive Charcot patients were treated by off-loading, and monitored for 2 years by repeated foot radiography, MRI, and circulating levels of sclerostin, dickkopf-1, Wnt inhibitory factor-1, Wnt ligand-1, OPG, and RANKL. 20 neuropathic diabetic controls and 20 healthy controls served as the reference. Results — Levels of sclerostin, Dkk-1 and Wnt-1, but not of Wif-1, were significantly lower in Charcot patients than in the diabetic controls at inclusion. Dkk-1 and Wnt-1 levels responded to off-loading by increasing. Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups. OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years. OPG/RANKL ratio was balanced in all groups at inclusion, and it remained balanced in Charcot patients on repeated measurement throughout the study. Interpretation — High plasma RANKL and OPG levels at diagnosis of Charcot suggest that there is high bone remodeling activity before gradually normalizing after off-loading treatment. The consistently balanced OPG/RANKL ratio in Charcot patients suggests that there is low-key net bone building activity by this pathway following diagnosis and treatment. Inter-group differences at diagnosis and changes in Wnt signaling following off-loading treatment were sufficiently large to be reflected by systemic levels, indicating that this pathway has a role in bone remodeling and bone repair activity in Charcot patients. This is of particular clinical relevance considering the recent emergence of promising drugs that target this system.
    Acta Orthopaedica 03/2015; DOI:10.3109/17453674.2015.1033606 · 2.45 Impact Factor
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    • "Studies have demonstrated that Dickkopf-1 (DKK-1) is capable of inhibiting the Wnt pathway. Osteoprotegerin (OP) can inhibit bone resorption by inhibiting osteoclast activation, blocking the effects of ligand of transcription factor of NF-kappa beta (RANKL) [13] [14] [15] [16]. However, the actual function of these markers and their correlation with SpA disease activity are not elucidated yet. "
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    ABSTRACT: Studies have demonstrated the important role of bone remodelling and osteoimmunology in the progression of inflammatory lesions in axial spondyloarthritis (SpA) disease. This study was conducted to evaluate the inflammatory response by analysis of the serum levels of pro-inflammatory and new bone formation markers in patients with axial SpA who were treated or not treated with anti-tumour necrosis factor-α (anti-TNF-α) or non-steroidal drugs (NSAIDs) and to identify whether these drugs modify the activity and severity of the disease. The serum levels of myeloperoxidase (MPO), adenosine deaminase (ADA), nitric oxide metabolites (NOx), bone alkaline phosphatase (BAP), Dickkopf-1 (DKK-1), and osteoprotegerin (OP) were measured in 52 SpA patients who were treated or not with anti-TNF-α or NSAIDs and in 26 healthy controls using colourimetric and enzyme immunoassay tests. The activity and the severity of illness in patients with SpA were assessed using questionnaires (Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)). A significant difference between the controls and the patients without medication was observed in relation to NOx, BAP, and OP (p < 0.01). When the patients were compared with regard to their treatment, there were no clinically significant differences between the groups (p > 0.05). In conclusion, The NOx, BAP, and OP are emerging as important inflammatory pathways in axial SpA. Also the anti-TNF-α or non-steroidal drugs reduce the inflammation and destructions, however these treatments do not modify the serum levels of these biomarkers.
    International Immunopharmacology 08/2014; 21(2):481–486. DOI:10.1016/j.intimp.2014.05.031 · 2.71 Impact Factor
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    • "The idea that Wnt/β-catenin signaling may restrict several aspects of inflammation is supported in several mammalian models of disease and injury. For example, high Dkk1 activity is associated with pro-inflammatory bone loss in mouse myelomas (Tian et al., 2003), and inhibition of Dkk1 activity in a mouse model of rheumatoid arthritis results in greater bone formation (Diarra et al., 2007). The role of Wnt/β-catenin signaling in modulating the injury response might indeed be similarly contextspecific in zebrafish; further study in other anatomical injury models would be beneficial in this context. "
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    ABSTRACT: Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Although recent evidence suggests that similar cells exist in zebrafish and also migrate to sites of injury in larvae, whether these cells are functionally important for wound healing or regeneration in adult zebrafish is unknown. To begin to address these questions, we first tracked neutrophils (lyzC(+), mpo(+)) and macrophages (mpeg1(+)) in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype. These results provide a cellular and molecular link between components of the inflammation response and regeneration in adult zebrafish.
    Development 07/2014; 141(13):2581-91. DOI:10.1242/dev.098459 · 6.27 Impact Factor
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