Diarra, D., Stolina, M., Polzer, K., Zwerina, J., Ominsky, M. S., Dwyer, D. et al. Dickkopf-1 is a master regulator of joint remodeling. Nat. Med. 13, 156-163

Maastricht University, Maestricht, Limburg, Netherlands
Nature Medicine (Impact Factor: 27.36). 03/2007; 13(2):156-63. DOI: 10.1038/nm1538
Source: PubMed


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
    • " 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.
    No preview · Article · Mar 2015 · Acta Orthopaedica
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    • "DKK-1 promotes internalization of the receptor complex and dampens the Wnt signal (51). This inhibition is potentiated in the presence of TNF-α (18, 19). However, our findings suggest that DKK-1 mRNA expression significantly decreased in the presence of TNF-α, which was associated with osteogenic induction. "
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    ABSTRACT: Objectives: Rheumatoid arthritis (RA) is characterized by defective bone repair and excessive destruction, and ankylosing spondylitis (AS) by increased ectopic bone formation with syndesmophytes. Since TNF-α and IL-17A are involved in both diseases, this study investigated their effects on the osteogenic differentiation of isolated human bone marrow derived mesenchymal stem cells (hMSCs). Methods: Differentiation of hMSCs into osteoblasts was induced in the presence or absence of IL-17A and/or TNF-α. Matrix mineralization (MM) was evaluated by alizarin red staining and alkaline phosphatase activity (ALP). mRNA expression was measured by qRTPCR for BMP2 and Runx2, genes associated with osteogenesis, of DKK1, a negative regulator of osteogenesis, of Schnurri-3 and RANKL, associated with the cross talk with osteoclasts, and of TNFRI and TNFRII. Results: TNF-α alone increased both MM and ALP activity. IL-17A alone increased ALP but not MM. Their combination was more potent. TNF-α alone increased BMP2 mRNA expression at 6 and 12hr. These levels decreased in combination with IL-17A at 6hr only. DKK1mRNA expression was inhibited by TNF-α and IL-17A either alone or combined. Supporting an imbalance towards osteoblastogenesis, RANKL expression was inhibited by TNF-α and IL-17A. However, TNF-α but not IL-17 alone decreased Runx2 mRNA expression at 6hr. In parallel, TNF-α but not IL-17 alone increased Schnurri-3 expression with a synergistic effect with their combination. This may be related to an increase of TNFRII overexpression. Conclusion: IL-17 increased the effects of TNF-α on bone matrix formation by hMSCs. However, IL-17 decreased the TNF-α -induced BMP2 inhibition. Synergistic interactions between TNF-α and IL-17 were seen for RANKL inhibition and Schnurri-3 induction. Such increase of Schnurri-3 may in turn activate osteoclasts leading to bone destruction as in RA. Conversely, in the absence of osteoclasts, this could promote ectopic bone formation as in AS.
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    • "Interestingly, we observed that the Sema4D-dependent migration and dedifferentiation of osteoblasts requires IKK-complex activity, thereby indicating that the significance of the identified IKK signalling mechanism is not only restricted to cancer cells but also extends to other non-malignant cell types. Beside enhanced osteoclastic bone resorption, a decrease in osteoblastic bone formation is observed in bone loss associated with inflammatory and neoplastic diseases [58],[59]. Since Sema4D is expressed in T-cells and certain types of cancer cells, Plexin-B1-mediated and IKK-complex-dependent RhoA activation might contribute to reduced bone formation under these circumstances. The IKK-complex might therefore represent a novel therapeutic target for the treatment of B-plexin-dependent tumours as well as in osteoporosis and other bone diseases. "
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    ABSTRACT: Plexins are widely expressed transmembrane proteins that mediate the cellular effects of semaphorins. The molecular mechanisms of plexin-mediated signal transduction are still poorly understood. Here we show that signalling via B-family plexins leading to the activation of the small GTPase RhoA requires activation of the IκB kinase (IKK)-complex. In contrast, plexin-B-dependent regulation of R-Ras activity is not affected by IKK activity. This regulation of plexin signalling depends on the kinase activity of the IKK-complex, but is independent of NF-κB activation. We confirm that the IKK-complex is active in tumour cells and osteoblasts, and we demonstrate that plexin-B-dependent tumour cell invasiveness and regulation of osteoblast differentiation require an active IKK-complex. This study identifies a novel, NF-κB-independent function of the IKK-complex and shows that IKK directs plexin-B signalling to the activation of RhoA.
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