Biological and mechanical effect of selective proinflammatory cytokine inhibition in degenerative disc disease
Dr. med. Gernot Lang & Prof. Dr. med. Norbert Südkamp Klinik für Orthopädie und Unfallchirurgie, Universitätsklinikum Freiburg, Deutschland,
04/2016 - 12/2019
Degeneration of the intervertebral disc accounts for up to 40% of all cases of low back pain. This project aims towards an in vitro model for degeneration and inflammation of the human disc.
Low back pain (LBP) is a major cause of morbidity leading to enormous costs for western health care systems. Recent studies established an association between LBP and degeneration of the intervertebral disc (IVD), accounting degenerative disc disease (DDD) for up to 40% of all LBP cases. The intervertebral disc contains the soft and gelatinous nucleus pulposus (NP), the surrounding fibrocartilaginous annulus fibrosus (AF), and the cartilaginous endplate (EP) which connects the IVD to the corpus vertebrae. <7p>
DDD is characterized by extracellular matrix (ECM) degradation, release of proinflammatory cytokines, altered spine biomechanics, angiogenesis and nerve ingrowth which is associated with increased pain sensation. DDD can be triggered and exacerbated by many factors, including mechanical stress, trauma, genetic predisposition and inflammati
IL-1β and TNF-α, two major proinflammatory cytokines, were shown to regulate the expression of A Disintegrin and Metalloprotease with Thrombospondin Motifs (ADAMTS), major catabolic enzymes for extracellular matrix deterioration, through activation of MAPK and NF-κB signaling, which leads to tissue degeneration. Regarding the association to pain, current research arises evidence TNF-α being neurotoxic, inducing pain behavioral changes, axonal and myelin injury, intravascular coagulation and increased vascular permeability. Targeting proinflammatory cytokines by minimally invasive application of their respective inhibitors could prevent further degeneration and development of chronic pain.
Since the IVD does not possess a sufficient self-repair capacity, current treatment options for DDD range from conservative treatments to invasive therapies for severe and symptomatic courses of DDD, like spinal fusion or total disc replacement, although long-term results do not show significant differences compared to conservative therapies and complications are common. Additionally, none of the current invasive techniques address the underlying biological pathology.
Therefore therapies that inhibit the expression of TNF-α and IL-1β may be a promising therapeutic approach to consider, aiming to reduce inflammation and maintain IVDs extracellular matrix.
The aim of our study is to (1) develop an IVD organ culture degeneration and inflammation model in order to mimic and investigate the inflammatory pathogenesis in early stage DDD. Additionally (2) we aim to assess the biological and mechanical effect of selective cytokine inhibition as a potential treatment alternative for DDD. The experiments will be conducted with an organ culture system under degenerative dynamic loading and proinflammatory conditions.
Lang G, Liu Y, Zhou Z, Kubosch D, Südkamp NP, Alini M, Grad S, Li Z. A proinflammatory and degenerative intervertebral disc organ culture model by combining TNF-α intradiscal injection and detrimental dynamic loading. Journal of Tissue Engineering and Regenerative Medicine, 2018
Pfannkuche JJ, Guo W, Cui S, Ma J, Lang G, Peroglio M, Richards RG, Alini M, Grad S, Li Z (2019) Intervertebral disc organ culture for the investigation of disc pathology and regeneration - benefits, limitations, and future directions of bioreactors. Connect Tissue Res:1-18. doi: 10.1080/03008207.2019.1665652
Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany
Medical School at the Ruhr-University-Bochum, Germany 2007-2013. Doctoral degree 2014. Postdoctoral Research Fellowship at the AO Research Institute Davos, Switzerland 2014-2015. Residency at the department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany. Since 2016 postdoctoral Spine Fellow at Weill Cornell Medical College, Department of Neurological Surgery, New York, USA.
Prof. Dr. med. Norbert Südkamp
Graduate Engineer (Dipl.-Ing.) at the Technische Universität Hannover 1969. Medical School Hannover 1975-1981. Research Assistant at the Department of Telecommunication, University of Hannover, Germany 1976-1980. Doctoral degree 1982. Habilitation 1990. Assistant Medical Director and Professor (C3) Department of Trauma Surgery, University Hospital Charité, Berlin, Germany 1992-2001. Acting Medical Director 2000-2001 Department of Trauma Surgery, University Medical Center Freiburg, Germany. Chief of Department of Trauma Surgery 2001-2005. Since 2005 Chief of Department of Orthopedics and Trauma Surgery.
Prof. Dr. Mauro Alini
Diploma in Chemistry at the University of Lausanne, Switzerland 1983. Ph.D. in Biochemistry University of Lausanne, Switzerland 1988. Principal Investigator Shriners Hospital, Montreal, Canada 1992-1995. Assistant Professor at the Orthopedic Division, McGill University, Montreal, Canada 1995-2000. Since 2000 Head of Musculoskeletal Regeneration Program at the AO Research Institute, Davos, Switzerland. Since 2009 Vice Director at the AO Research Institute, Davos, Switzerland.
Dr. Sibylle Grad
Federal Diploma in Pharmacy at the Institute of Pharmacy, ETH Zürich, Switzerland; Ph.D. in Natural Sciences at the Institute of Clinical Chemistry, University Hospital, Zürich, and Institute of Cell Biology, ETH Zürich, Switzerland, 1999. Postdoc at the Scripps Research Institute, La Jolla, CA, USA 1999-2000; Postdoc and Research Scientist at the AO Research Institute Davos, Switzerland 2000-2009; Visiting Research Scientist Tokai University School of Medicine, Japan 2006; since 2009 Principal Scientist and deputy Program Head of intervertebral disc and cartilage research at the AO Research Institute Davos, Switzerland.
Dr. Zhen Li
Bachelor in Bioengineering at the Chu Kechen Honors College, Zhejiang University, Hangzhou, China 2001-2005. Ph.D. in Biochemical Engineering at the Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China 2005-2010 and at the AO Research Institute Davos, Switzerland 2006-2009. Lecturer Shandong University School of Medicine, Jinan, China 2010. Postdoc at the AO Research Institute Davos, Switzerland 2011-2013. Since 2013 Research Scientist at the AO Research Institute Davos, Switzerland.
Dr. med. David-Christopher Kubosch
Medical School at the Georg-August-Universität Göttingen, Germany 1997-2003. Arzt im Praktikum at the Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany 2003-2005. Resident at the Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany 2005-2015. Doctoral degree 2009. Since 2009 attending Orthopedic and Trauma surgeon.
Medical School at the Tongji Medical College of HUST (Huazhong University of Science and Technology), Wuhan, China 2010-2012. Since 2012 Medical School at the Albert-Ludwigs-Universität Freiburg, Germany. Since 2016 MD candidate at the Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany.
Bachelor of Science (Sport and Exercise Science) University of Bedforshire, UK / University of the Sunshine Coast, Queensland 2004-2007. Since 2011 Medical School at the Albert-Ludwigs-Universität Freiburg, Germany. der Albert-Ludwigs-Universität Freiburg. Since 2016 MD candidate at the Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany.
Medical School at the Christian-Albrechts-Universität Kiel, Germany since 2013. Since 2016 MD candidate at the Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany.