IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis

Shaw, A.; Maeda, Yukiko; Gravallese, Ellen M.

doi:10.1186/s13075-016-0998-x

Cited by 74 publications

(56 citation statements)

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“…Cytokines produced by Th17 cells can drive the differentiation of osteoclasts from precursors and these osteoclasts can tip the balance in the direction of bone resorption [29]. In addition to osteoclast increase, a recent study has shown that IL-17A can decrease osteoblast formation resulting in a net bone loss [30]. …”

Section: Discussionmentioning

confidence: 99%

Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis

et al. 2016

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BackgroundThe linkage between periodontal disease and rheumatoid arthritis is well established. Commonalities among the two are that both are chronic inflammatory diseases characterized by bone loss, an association with the shared epitope susceptibility allele, and anti-citrullinated protein antibodies.MethodsTo explore immune mechanisms that may connect the two seemingly disparate disorders, we measured host immune responses including T-cell phenotype and anti-citrullinated protein antibody production in human leukocyte antigen (HLA)-DR1 humanized C57BL/6 mice following exposure to the Gram-negative anaerobic periodontal disease pathogen Porphyromonas gingivalis. We measured autoimmune arthritis disease expression in mice exposed to P. gingivalis, and also in arthritis-resistant mice by flow cytometry and multiplex cytokine-linked and enzyme-linked immunosorbent assays. We also measured femoral bone density by microcomputed tomography and systemic cytokine production.ResultsExposure of the gingiva of DR1 mice to P. gingivalis results in a transient increase in the percentage of Th17 cells, both in peripheral blood and cervical lymph nodes, a burst of systemic cytokine activity, a loss in femoral bone density, and the generation of anti-citrullinated protein antibodies. Importantly, these antibodies are not produced in response to P. gingivalis treatment of wild-type C57BL/6 mice, and P. gingivalis exposure triggered expression of arthritis in arthritis-resistant mice.ConclusionsExposure of gingival tissues to P. gingivalis has systemic effects that can result in disease pathology in tissues that are spatially removed from the initial site of infection, providing evidence for systemic effects of this periodontal pathogen. The elicitation of anti-citrullinated protein antibodies in an HLA-DR1-restricted fashion by mice exposed to P. gingivalis provides support for the role of the shared epitope in both periodontal disease and rheumatoid arthritis. The ability of P. gingivalis to induce disease expression in arthritis-resistant mice provides support for the idea that periodontal infection may be able to trigger autoimmunity if other disease-eliciting factors are already present.

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Section: Discussionmentioning

confidence: 99%

Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis

et al. 2016

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“…In contrast, periosteal lamellar bone deposition occurs much more slowly, in agreement with a progression of melorheostotic lesions over years . Periosteal new bone formation is often viewed as a physiological response to focal insults or systemic condition such as infections, hemorrhages, inflammations (periostitis), osteonecrosis, tumor processes, and malign neoplasms such as Ewing's sarcoma or Caffey's disease . In fact, so‐called “periosteal reactions” occur widely and represent a rather nonspecific mechanism to maintain bone strength, counteracting the effects of cortical lysis or endocortical bone loss by forming a bridge over damaged cortical area .…”

Section: Discussionmentioning

confidence: 96%

“…We do not currently know the factors that drive the periosteal reaction in the melorheostosis lesion. It is, however, interesting that inflammation seems to act as a strong local stimulus . In that sense, it seems possible that inflammatory cytokines produced during overactive bone remodeling also trigger periosteal bone formation.…”

Section: Discussionmentioning

confidence: 99%

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

Fratzl‐Zelman

Roschger

Kang

et al. 2019

Journal of Bone and Mineral Research

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Melorheostosis is a rare non‐hereditary condition characterized by dense hyperostotic lesions with radiographic “dripping candle wax” appearance. Somatic activating mutations in MAP2K1 have recently been identified as a cause of melorheostosis. However, little is known about the development, composition, structure, and mechanical properties of the bone lesions. We performed a multi‐method phenotype characterization of material properties in affected and unaffected bone biopsy samples from six melorheostosis patients with MAP2K1 mutations. On standard histology, lesions show a zone with intensively remodeled osteonal‐like structure and prominent osteoid accumulation, covered by a shell formed through bone apposition, consisting of compact multi‐layered lamellae oriented parallel to the periosteal surface and devoid of osteoid. Compared with unaffected bone, melorheostotic bone has lower average mineralization density measured by quantitative backscattered electron imaging (CaMean: –4.5%, p = 0.04). The lamellar portion of the lesion is even less mineralized, possibly because the newly deposited material has younger tissue age. Affected bone has higher porosity by micro‐CT, due to increased tissue vascularity and elevated 2D‐microporosity (osteocyte lacunar porosity: +39%, p = 0.01) determined on quantitative backscattered electron images. Furthermore, nano‐indentation modulus characterizing material hardness and stiffness was strictly dependent on tissue mineralization (correlation with typical calcium concentration, CaPeak: r = 0.8984, p = 0.0150, and r = 0.9788, p = 0.0007, respectively) in both affected and unaffected bone, indicating that the surgical hardness of melorheostotic lesions results from their lamellar structure. The results suggest a model for pathophysiology of melorheostosis caused by somatic activating mutations in MAP2K1, in which the genetically induced gradual deterioration of bone microarchitecture triggers a periosteal reaction, similar to the process found to occur after bone infection or local trauma, and leads to an overall cortical outgrowth. The micromechanical properties of the lesions reflect their structural heterogeneity and correlate with local variations in mineral content, tissue age, and remodeling rates, in the same way as normal bone. © 2018 American Society for Bone and Mineral Research

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“…However, when inflammatory conditions are present, IL‐17A drives osteoclastogenic effects by disrupting the RANKL/RANK/OPG axis . It has been shown that IL‐17A deficiency resulted in increased periosteal bone formation in the K/BxN serum transfer model of inflammatory arthritis . This finding might seem contradictory to the IL‐17A–dependent increased bone regeneration in the drill‐hole injury animal model .…”

Section: Animal Models Showing a Role For Il‐23 In Enthesitismentioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis

Cited by 74 publications

References 50 publications

Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis

Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

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