Lories, R. J. U., Derese, I. & Luyten, F. P. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J. Clin. Invest. 115, 1571-1579

Laboratory for Skeletal Development and Joint Disorders, Department of Rheumatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
Journal of Clinical Investigation (Impact Factor: 13.22). 07/2005; 115(6):1571-9. DOI: 10.1172/JCI23738
Source: PubMed


Joint ankylosis is a major cause of disability in the human spondyloarthropathies. Here we report that this process partially recapitulates embryonic endochondral bone formation in a spontaneous model of arthritis in DBA/1 mice. Bone morphogenetic protein (BMP) signaling appears to be a key molecular pathway involved in this pathological cascade. Systemic gene transfer of noggin, a BMP antagonist, is effective both as a preventive and a therapeutic strategy in the mouse model, mechanistically interfering with enthesial progenitor cell proliferation in early stages of the disease process. Immunohistochemical staining for phosphorylated smad1/5 in enthesial biopsies of patients with spondyloarthropathy reveals active BMP signaling in similar target cells. Our data suggest that BMP signaling is an attractive therapeutic target for interfering with structural changes in spondyloarthropathy either as an alternative or complementary approach to current antiinflammatory treatments.

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    • "Old male DBA/1 mice develop peripheral arthritis and it has been shown that noggin (NOG) can rescue the enthesopathy.92 In contrast, we showed that NOG treatment of ank/ank mice led to more severe ankylosis, with concurrent generation of high levels of immunoglobulin (Ig)-G immune complexes (ICs) in which the autoantigens are either NOG (a bone morphogenetic protein-signaling antagonist) or SOST (a Wnt/β-catenin signaling antagonist).93 "
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    ABSTRACT: Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage-bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS.
    The Application of Clinical Genetics 05/2014; 7:105-15. DOI:10.2147/TACG.S37325
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    • "Syndesmophytes, which are one of the radiographic hallmarks of the SpAs, represent examples of ossification at the margins of vertebral bodies that are formed via the process of endochondral ossification [10]. Local production of bone growth factors, including TGF-β and BMPs, which play a role in endochonral bone formation during development and post-natally in fracture repair, have been implicated in this process [10–14]. "
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    ABSTRACT: The seronegative spondyloarthopathies (SpA) share certain common articular and peri-articular features that differ from rheumatoid arthritis (RA) and other forms of inflammatory arthritis. These include the tendency of the SpAs to involve the axial skeleton in addition to the diarthrodial joints, and the prominent involvement of the extra-articular entheses (sites of ligamentous and tendon insertion), which are not common sites of primary pathology in RA and other inflammatory arthropathies. The differential anatomic sites of bone pathology in the SpAs in comparison to the other forms of arthritis suggest that the underlying pathogenic processes and cellular and molecular mechanisms that account for the peri-articular bone pathology involve different underlying disease mechanisms. This review will highlight the molecular and cellular processes that are involved in the pathogenesis of the skeletal pathology in the SpAs, and provide evidence that many of the factors involved in regulation of bone cell function exhibit potent immune-regulatory activity, providing support for the general concept of osteoimmunology.
    Current Rheumatology Reports 07/2013; 15(7):342. DOI:10.1007/s11926-013-0342-2 · 2.87 Impact Factor
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    • "Recent studies reveal that the canonical and non-canonical Wnt signaling play important roles in the process of fracture healing and bone regeneration both in the appendicular skeleton and craniofacial skeleton (Hadjiargyrou et al., 2002; Zhong et al., 2006; Chen et al., 2007; Kakar et al., 2007; Kim et al., 2007; Leucht et al., 2008). In addition, for ankylosing spondylitis, the best-known form of spondyloarthritis , the molecular mechanism underlying ankylosis is hypothesized to recapitulate the process of endochondral bone formation (Lories et al., 2005, 2009; Braem and Lories, 2012; Carter et al., 2012) and the Wnt signaling has been shown to contribute to the progression of the condition (Diarra et al., 2007; Appel et al., 2009; Daoussis et al., 2010; Uderhardt et al., 2010; Heiland et al., 2012; Zhao et al., 2012). Therefore we hypothesize that the Wnt signaling may also involve in the development of traumatic TMJ bony ankylosis. "
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    ABSTRACT: OBJECTIVE: To preliminarily investigate the temporal patterns of the endogenous mRNA expression for members of the Wnt signaling and a series of genes regulating bone formation during the development of traumatic temporomandibular joint (TMJ) bony ankylosis in a sheep model. METHODS: Six sheep were used for the induction of bony ankylosis of TMJ. We performed a condylar fracture, excision of the lateral 2/3 disc and serious injury to the glenoid fossa to induce bony ankylosis on the right TMJ. An isolated condylar fracture was performed on the left side. Two sheep were sacrificed at 1 month, 3 months, and 6 months after surgery, respectively. The specimens from the ankylosed joint and the condylar fracture were harvested for RNA extraction respectively. In this report (Part I), only the bony ankylosed samples were used for analysis of gene expressions. The specimens 1 month postoperatively were taken as the control, and the changes of expression of target genes over time were examined by real-time PCR. RESULTS: mRNA expression of Wnt1, Wnt2b, Wnt3a, β-catenin, Sfrp1, Lrp6, Lef1, CyclinD1, and Runx2 was up-regulated at 3 and 6 months compared with 1 month. The expression of Wnt5a, Sox9, and Osterix was up-regulated with a peak at 3 months, and then fell back to the basal levels at 6 months. The expression of Ocn began to up-regulate until 6 month postoperatively. CONCLUSION: Our findings suggested that Wnt signaling was involved in the formation of traumatic TMJ bony ankylosis and thus may be a potential therapeutic target for the treatment of the disease in the future.
    Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo-Facial Surgery 05/2013; 42(2). DOI:10.1016/j.jcms.2013.04.009 · 2.93 Impact Factor
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