Neng-Yu Lin1, Alfiya Distler1, Christian Beyer1, Ariella Philipi-Schöbinger1, Silvia Breda2, Clara Dees1, Michael Stock1, Michal Tomcik3, Andreas Niemeier4, Francesco Dell'Accio5, Kolja Gelse6, Mark P Mattson7, Georg Schett1, Jörg Hw Distler1. 1. Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany. 2. Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 3. Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic. 4. Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary, University of London, London, UK. 6. Division of Trauma Surgery and Orthopedic Surgery, Department of Surgery, University of Erlangen-Nuremberg, Germany. 7. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Jean De La Croix Ndong; Yvonne Stephenson; Michael E Davis; Andrés J García; Steven Goudy Journal: J Biomed Mater Res A Date: 2017-11-15 Impact factor: 4.396
Authors: Chathuraka T Jayasuriya; Nan Hu; Jing Li; Nicholas Lemme; Richard Terek; Michael G Ehrlich; Qian Chen Journal: Sci Rep Date: 2018-05-04 Impact factor: 4.379