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Autophagy regulates TNFα-mediated joint destruction in experimental arthritis
  1. Neng-Yu Lin1,
  2. Christian Beyer1,
  3. Andreas Gießl2,
  4. Trayana Kireva1,
  5. Carina Scholtysek1,3,
  6. Stefan Uderhardt1,3,
  7. Luis Enrique Munoz1,
  8. Clara Dees1,
  9. Alfiya Distler1,
  10. Stefan Wirtz4,
  11. Gerhard Krönke1,3,
  12. Brian Spencer5,
  13. Oliver Distler6,
  14. Georg Schett1,
  15. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Biology, Animal Physiology, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
  4. 4Department of Internal Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany
  5. 5Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
  6. 6Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to  Dr Jörg H W Distler, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, PO Box Glücksstr.4a, Erlangen D-91054, Germany; joerg.distler{at}


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 real-time 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.

  • Arthritis
  • Rheumatoid Arthritis
  • TNF-alpha

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