Autophagy regulates TNFα-mediated joint destruction in experimental arthritis

Lin NY, Beyer C, Gießl A, Kireva T, Scholtysek C, Uderhardt S, Munoz LE, Dees C, Distler A, Wirtz S, Krönke G, Spencer B, Distler O, Schett G, Distler J (2013)

Publication Type: Journal article

Publication year: 2013

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 72

Pages Range: 761-768

Journal Issue: 5

DOI: 10.1136/annrheumdis-2012-201671

Abstract

Objectives: Autophagy is a homeostatic process to recycle dispensable and damaged cell organelles. Dysregulation of autophagic pathways has recently been implicated in the pathogenesis of various diseases. Here, we investigated the role of autophagy during joint destruction in arthritis. Methods: Autophagy in osteoclasts was analysed in vitro and ex vivo by transmission electron microscopy, Western blotting and immunohistochemistry for Beclin1 and Atg7. Small molecule inhibitors, LysMCre-mediated knockout of Atg7 and lentiviral overexpression of Beclin1 were used to modulate autophagy in vitro and in vivo. Osteoclast differentiation markers were quantified by realtime PCR. The extent of bone and cartilage destruction was analysed in human tumour necrosis factor α transgenic (hTNFα tg) mice after adoptive transfer with myeloid specific Atg7-deficient bone marrow. Results: Autophagy was activated in osteoclasts of human rheumatoid arthritis (RA) showing increased expression of Beclin1 and Atg7. TNFα potently induced the expression of autophagy-related genes and activated autophagy in vitro and in vivo. Activation of autophagy by overexpression of Beclin1-induced osteoclastogenesis and enhanced the resorptive capacity of cultured osteoclasts, whereas pharmacologic or genetic inactivation of autophagy prevented osteoclast differentiation. Arthritic hTNFα tg mice transplanted with Atg7fl/fl×LysMCre+ bone marrow cells (BMC) showed reduced numbers of osteoclasts and were protected from TNFα-induced bone erosion, proteoglycan loss and chondrocyte death. Conclusions: These findings demonstrate that autophagy is activated in RA in a TNFα-dependent manner and regulates osteoclast differentiation and bone resorption. We thus provide evidence for a central role of autophagy in joint destruction in RA.

Authors with CRIS profile

Christian Beyer Department of Medicine 3 – Rheumatology and Immunology Andreas Gießl Lehrstuhl für Tierphysiologie Stefan Uderhardt Department of Medicine 3 – Rheumatology and Immunology Luis Munoz Becerra Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Gerhard Krönke Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Involved external institutions

University of California, San Diego US United States (USA) (US) Universitätsspital Zürich (USZ) CH Switzerland (CH)

How to cite

APA:

Lin, N.-Y., Beyer, C., Gießl, A., Kireva, T., Scholtysek, C., Uderhardt, S.,... Distler, J. (2013). Autophagy regulates TNFα-mediated joint destruction in experimental arthritis. Annals of the Rheumatic Diseases, 72(5), 761-768. https://doi.org/10.1136/annrheumdis-2012-201671

MLA:

Lin, Neng-Yu, et al. "Autophagy regulates TNFα-mediated joint destruction in experimental arthritis." Annals of the Rheumatic Diseases 72.5 (2013): 761-768.

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