Project 059

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 - 03/2018

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

Extracellular matrix content of the intervertebral disc.
NP: Nucleus pulposus; AF: Annulus fibrosus; ECM: Extracellular matrix

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.

Institutions

Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Germany

AO Research Institute Davos, Davos, Switzerland

Duration

04/2016 - 03/2018

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