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RESEARCH ARTICLE
Mast cells enhance sterile inflammation in chronic nonbacterial osteomyelitis
Stephanie Young, Namit Sharma, Jae Hoon Lee, Violeta Chitu, Volker Neumeister, Elisabeth Sohr, E. Richard Stanley, Christian M. Hedrich, Andrew W. B. Craig
Disease Models & Mechanisms 2019 12: dmm040097 doi: 10.1242/dmm.040097 Published 20 August 2019
Stephanie Young
1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
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Namit Sharma
1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
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Jae Hoon Lee
1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
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Violeta Chitu
2Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Volker Neumeister
3Departments of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden 01307, Germany
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Elisabeth Sohr
4Pediatric Rheumatology and Immunology, Children's Hospital Dresden, Technical University Dresden, Dresden 01307, Germany
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E. Richard Stanley
2Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Christian M. Hedrich
4Pediatric Rheumatology and Immunology, Children's Hospital Dresden, Technical University Dresden, Dresden 01307, Germany
5Department of Women's & Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool L14 5AB, UK
6Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool L14 5AB, UK
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Andrew W. B. Craig
1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
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  • For correspondence: andrew.craig@queensu.ca
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ABSTRACT

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease, and patients with active or recurrent bone inflammation at multiple sites are diagnosed with chronic recurrent multifocal osteomyelitis (CRMO). The Chronic multifocal osteomyelitis (CMO) mouse model develops IL-1β-driven sterile bone lesions reminiscent of severe CRMO. The goal of this study was to evaluate the potential involvement of mast cells in CMO/CRMO. Here, we show that mast cells accumulate in inflamed tissues from CMO mice and that mast cell protease Mcpt1 can be detected in the peripheral blood. A transgenic model of connective tissue mast cell depletion (Mcpt5-Cre:Rosa26-Stopfl/fl-DTa) was crossed with CMO mice and the resulting mice (referred to as CMO/MC–) showed a significant delay in disease onset compared with age-matched CMO mice. At 5-6 months of age, CMO/MC– mice had fewer bone lesions and immune infiltration in the popliteal lymph nodes that drain the affected tissues. In bone marrow-derived mast cell cultures from CMO mice, cytokine production in response to the alarmin IL-33 was elevated compared with wild-type cultures. To test the relevance of mast cells to human CRMO, we tested serum samples from a cohort of healthy controls and from CRMO patients at diagnosis. Interestingly, mast cell chymase was elevated in CRMO patients as well as in patients with oligoarticular juvenile arthritis. Tryptase-positive mast cells were also detected in bone lesions from CRMO patients and patients with bacterial osteomyelitis. Together, our results identify mast cells as cellular contributors to bone inflammation in CMO/CRMO and provide rationale for further study of mast cells as therapeutic targets.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Conceptualization: A.W.C.; Methodology: A.W.C.; Formal analysis: J.L., C.H., A.W.C.; Investigation: S.Y., N.S., J.L., V.N., E.S., C.H.; Resources: V.C., R.S., C.H.; Data curation: S.Y.; Writing - original draft: J.L., A.W.C.; Writing - review & editing: S.Y., N.S., V.C., R.S., C.H., A.W.C.; Supervision: A.W.C.; Project administration: A.W.C.; Funding acquisition: A.W.C.

  • Funding

    This research was supported by an operating grant from Canadian Institutes for Health Research (CIHR; MOP 82882) to A.W.B.C., National Institutes of Health grant CA32551 to E.R.S., and grants from the Fritz Thyssen Stiftung (10.15.1.019), and the intramural MeDDrive program (60.364) of TU Dresden to C.M.H.

  • Supplementary information

    Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.040097.supplemental

  • Received April 9, 2019.
  • Accepted July 21, 2019.
  • © 2019. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/4.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Autoinflammation
  • Chronic recurrent multifocal osteomyelitis
  • Cytokines
  • Interleukin-1β
  • Bone disease
  • CNO

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RESEARCH ARTICLE
Mast cells enhance sterile inflammation in chronic nonbacterial osteomyelitis
Stephanie Young, Namit Sharma, Jae Hoon Lee, Violeta Chitu, Volker Neumeister, Elisabeth Sohr, E. Richard Stanley, Christian M. Hedrich, Andrew W. B. Craig
Disease Models & Mechanisms 2019 12: dmm040097 doi: 10.1242/dmm.040097 Published 20 August 2019
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RESEARCH ARTICLE
Mast cells enhance sterile inflammation in chronic nonbacterial osteomyelitis
Stephanie Young, Namit Sharma, Jae Hoon Lee, Violeta Chitu, Volker Neumeister, Elisabeth Sohr, E. Richard Stanley, Christian M. Hedrich, Andrew W. B. Craig
Disease Models & Mechanisms 2019 12: dmm040097 doi: 10.1242/dmm.040097 Published 20 August 2019

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