Original Research ARTICLE
mTOR blockade by rapamycin in spondyloarthritis: impact on inflammation and new bone formation in vitro and in vivo
- 1Department of Experimental Immunology, University Medical Center Amsterdam, Netherlands
- 2Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, University of Amsterdam, Netherlands
- 3Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, United States
- 4Department of Internal Medicine, Rheumatic Diseases Division, UT Southwestern Medical Center, United States
Introduction: Spondyloarthritis (SpA) is characterized by inflammation, articular bone erosions and pathologic new bone formation. Targeting TNF or IL-17A with current available therapies reduces inflammation in SpA; however, treatment of the bone pathology remains an unmet clinical need. The Mammalian Target Of Rapamycin (mTOR) promotes IL-17 expression and osteogenesis and could therefore be a promising therapeutic target in SpA.
Objectives: To investigate whether blocking mTOR with rapamycin inhibits inflammation, bone erosions and new bone formation in SpA.
Methods: Peripheral blood mononuclear cells (PBMCs) from patients with SpA were stimulated with anti-CD3/CD28 in the presence or absence of rapamycin and cytokine expression was assessed. Fibroblast-like synoviocytes from SpA patients were cultured in osteogenic conditions with TNF, IL-17A or TNF plus IL-17 in the presence or absence of rapamycin and were assessed for differentiation. HLA-B27/Huβ2m transgenic rats were immunized with low dose heat-inactivated Mycobacterium tuberculosis (M.tub) and treated with 1.5 mg/kg rapamycin or vehicle prophylactically or therapeutically and monitored for arthritis and spondylitis. Histology and mRNA analysis were performed after 5 weeks of treatment.
Results: In vitro TNF and IL-17A protein production by SpA PBMCs was inhibited in the presence of rapamycin. Rapamycin also inhibited osteoblastic differentiation of human SpA FLS. Ex vivo analysis of SpA synovial biopsies indicated activation of the mTOR pathway in the synovial tissue of SpA patients. In vivo, prophylactic treatment of HLA-B27/Huβ2m transgenic rats with rapamycin significantly inhibited the development and severity of inflammation in peripheral joints and spine (arthritis and spondylitis), with histological evidence of reduced bone erosions and new bone formation around peripheral joints. In addition, therapeutic treatment with rapamycin significantly decreased severity of arthritis and spondylitis, with peripheral joint histology showing reduced inflammation, bone erosions and new bone formation. IL-17A mRNA expression was inhibited in the metacarpophalangeal joints after rapamycin treatment.
Conclusion: mTOR blockade inhibits IL-17A and TNF production by PBMCs and osteoblastic differentiation of FLS from patients with SpA in vitro. In the HLA-B27 transgenic rat model of SpA, rapamycin inhibits arthritis and spondylitis development and severity, reduces articular bone erosions, decreases pathologic new bone formation and suppresses IL-17A expression.
Keywords: Spondyloarthritis, rapamycin, Fibroblast like synovial cells, IL-17, Osteogenesis, Inflammation Immunomodulation
Received: 11 Jul 2019;
Accepted: 17 Sep 2019.
Copyright: © 2019 Chen, van Tok, Knaup, Kraal, Pots, Gravallese, Taurog, van de Sande, van Duivenvoorde and Baeten. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
MD. Sijia Chen, University Medical Center Amsterdam, Department of Experimental Immunology, Amsterdam, Netherlands, S.Chen@amc.uva.nl
PhD. Leonie M. van Duivenvoorde, University Medical Center Amsterdam, Department of Experimental Immunology, Amsterdam, Netherlands, email@example.com