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Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis
  1. Neng-Yu Lin1,
  2. Alfiya Distler1,
  3. Christian Beyer1,
  4. Ariella Philipi-Schöbinger1,
  5. Silvia Breda1,2,
  6. Clara Dees1,
  7. Michael Stock1,
  8. Michal Tomcik3,
  9. Andreas Niemeier4,
  10. Francesco Dell'Accio5,
  11. Kolja Gelse6,
  12. Mark P Mattson7,
  13. Georg Schett1,
  14. Jörg HW Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
  3. 3Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
  4. 4Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  5. 5William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary, University of London, London, UK
  6. 6Division of Trauma Surgery and Orthopedic Surgery, Department of Surgery, University of Erlangen-Nuremberg, Germany
  7. 7Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice.

Methods Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments.

Results Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1.

Conclusions Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.

  • Osteoarthritis
  • Chondrocytes
  • Knee Osteoarthritis

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors Design of the study: N-YL, JHWD. Acquisition of data: N-YL, AD, CB, APS, CD, MT, FD, KG. Interpretation of data: N-YL, AD, APS, CB, CD, MT, FD, KG, OD, GS, JHWD. Manuscript preparation: N-YL, JHWD. Provided samples and mice: AN, KG, MPM.

  • Funding This study was supported by grants A57, J29 and J39 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen, grants from the German Research Foundation (DI 1537/5–1, DI 1537/7-1, DI 1537/8-1, DI 1537/9-1, DE 2414/2-1 of the Deutsche Forschungsgemeinschaft), a grant of the ELAN-Foundation Erlangen to NYL and project grants 00023728 from the Ministry of Health of the Czech Republic and SVV262512. The study was also supported by the IMI-funded project BTCure, the carrier support award of the Ernst-Jung Foundation, the BMBF project ANCYLOSS and the Intramural Research Program of the National Institute on Aging. Neng-Yu Lin had a doctoral scholarship by Bavarian Research Foundation.

  • Competing interests JHWD has consultancy relationships and/or has received research funding from Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma and Active Biotech in the area of potential treatments of SSc and is stock owner of 4D Science GmbH.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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