Article

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

ABSTRACT

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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    • "BMP bone morphogenetic protein; RANKL receptor activator of nuclear factor κB ligand, RPKM reads per kilobase per million reads, TRAP tartrate-resistant acid phosphatase, CatK cathepsin K, DKK-1 dickkopf 1, TGF-β1 transforming growth factor β1 BMP2, which is a growth factor that stimulates chondrocyte differentiation as well as osteoblast differentiation , has been implicated in the process of bone formation and ankylosis in the DBA/1 enthesitis model. Thus, inhibition of BMP signaling by overexpression of noggin, which is an endogenous BMP antagonist, inhibited the onset and the progression of enthesitis[27]. In our study, BMP2 and BMP7 were downregulated within the arthritic paw, which is similar to findings in the collagen-induced arthritis model[28]. While BMPs were downregulated, we found upregulation of TGF-β1 after acute inflammation in DTHA had subsided. "
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    ABSTRACT: Background: The aims of the present study were to determine the relationship between bone destruction and bone formation in the delayed-type hypersensitivity arthritis (DTHA) model and to evaluate the effect of receptor activator of nuclear factor κB ligand (RANKL) blockade on severity of arthritis, bone destruction, and bone formation. Methods: DTHA was induced in C57BL/6 mice. Inflammation, erosive joint damage, and new bone formation were semiquantitatively scored by histology. Osteoclast activity was assessed in vivo, and messenger RNA (mRNA) expression of mediators of bone destruction and bone formation were analyzed by mRNA deep sequencing. Serum concentrations of tartrate-resistant acid phosphatase 5b, carboxy-terminal telopeptide I (CTX-I), matrix metalloproteinase 3 (MMP3), and serum amyloid P component (SAP) were determined by enzyme-linked immunosorbent assay. Anti-RANKL monoclonal antibody treatment was initiated at the time of immunization. Results: Bone destruction (MMP3 serum levels, cathepsin B activity, and RANKL mRNA) peaked at day 3 after arthritis induction, followed by a peak in cartilage destruction and bone erosion on day 5 after arthritis induction. Periarticular bone formation was observed from day 10. Induction of new bone formation indicated by enhanced Runx2, collagen X, osteocalcin, MMP2, MMP9, and MMP13 mRNA expression was observed only between days 8 and 11. Anti-RANKL treatment resulted in a modest reduction in paw and ankle swelling and a reduction of serum levels of SAP, MMP3, and CTX-I. Destruction of the subchondral bone was significantly reduced, while no effect on bone formation was seen. Conclusions: Anti-RANKL treatment prevents joint destruction but does not prevent new bone formation in the DTHA model. Thus, although occurring sequentially during the course of DTHA, bone destruction and bone formation are apparently not linked in this model.
    Full-text · Article · Dec 2016 · Arthritis research & therapy
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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.
    Full-text · Article · May 2014 · The Application of Clinical Genetics
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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.
    Full-text · Article · Jul 2013 · Current Rheumatology Reports
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