Inflammatory Mediators as Potential Therapeutic Targets in the Spine

Abstract

Inflammation plays a variable part in the pathogenesis of several spinal disorders. Ankylosing spondylitis is a chronic inflammatory arthropathy of the spine and rheumatoid arthritis, whilst affecting predominantly limb joints, also affects the cervical spine in a significant proportion of people. Inflammation is also involved in disorders such as disc herniation and sciatica, which have previously been thought of as being primarily mechanical or degenerative. Anti-inflammatory agents which have been shown to be effective elsewhere in the body are discussed in this review as possible therapeutic agents in the spine. As the inflammatory cascade and immunopathology of these conditions continue to be elucidated, it has become apparent that individual molecules may be potential targets for inactivation or down-regulation. Candidates include pro-inflammatory cytokines, such as TNF-alpha, cytokines, e.g. IL-1 and IL-15, or enzymes enhancing the inflammation pathway such as the cyclooxygenases. Hence treatments based on inactivation of these molecules by various mechanisms, including antibodies, receptor antagonists, enzyme inhibitors or gene therapy, are being introduced. However, the mode of action of a particular molecule can be complex and sometimes apparently contradictory. For example, TNF-alpha is known to play an important role in promoting inflammation by upregulating expression of cell adhesion molecules on endothelial cells and stimulating the production of reactive oxygen intermediates, nitric oxide and prostaglandins. However, it can also have an immunosuppressive and anti-inflammatory role after prolonged release. Therefore, although inhibitors of many of these molecules are now in clinical application and trials (many with promising results in rheumatoid arthritis), it is important to remain vigilant and monitor long-term outcomes particularly when these treatments are used in clinical syndromes with relatively poorly defined immunopathology such as spinal disorders.

Evaluation of inflammation and oxidative stress in ankylosing spondylitis: a role for macrophage migration inhibitory factor

“…Nitric oxide and MDA are good indicators of oxidative stress and lipid peroxidation. It has been reported that serum and synovial fluid NO levels increase in chronic inflammatory conditions, such as RA and osteoarthritis (OA) and degenerative disc diseases [18,19]. The production of NO can be induced by several inflammatory cytokines, including IL-1 and TNF-a.…”

“…MIF has been reported to be critical in the pathogenesis of autoimmune diseases, such as autoimmune diabetes, by inducing the production of NO [17]. It has also been suggested that NO is involved in the pathogenesis of rheumatic diseases [18,19], but the association of AS with commonly known oxidative stress markers and cytokines remains uncertain at this time.…”

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

“…The foremost contributors in patients with rheumatoid arthritis and related spondyloarthropathies are interleukin-1 (IL-1; chiefly the inducible β form) and tumor necrosis factor-α (TNFα) [4][5][6][7]. Their central importance is demonstrated by the ability of anti-IL-1 or anti-TNF-α biologics to reduce clinical and structural measures of disease in arthritic patients [8,9] and animals with induced arthritis [10][11][12][13][14][15].…”

p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL‐1

“…5 Altered biomechanical forces in the human cervical spine can upregulate IL-1 and TNF-a, 6 and Chubinskaya et al recently reported increases in these factors in discs of chronically compressed rat spine. 7 Le Maitre et al showed increasing IL-1 in human lumbar disc cells with increasing grade of degeneration.…”