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Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis.

AbstractINTRODUCTION:
Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury. To investigate the role of local and systemic inflammation in the development of post-traumatic arthritis, we targeted both the initial acute local inflammatory response and a prolonged 4 week systemic inflammatory response by inhibiting IL-1 or TNF-α following articular fracture in the mouse knee.
METHODS:
Anti-cytokine agents, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor II (sTNFRII), were administered either locally via an acute intra-articular injection or systemically for a prolonged 4 week period following articular fracture of the knee in C57BL/6 mice. The severity of arthritis was then assessed at 8 weeks post-injury in joint tissues via histology and micro computed tomography, and systemic and local biomarkers were assessed in serum and synovial fluid.
RESULTS:
Intra-articular inhibition of IL-1 significantly reduced cartilage degeneration, synovial inflammation, and did not alter bone morphology following articular fracture. However, systemic inhibition of IL-1, and local or systemic inhibition of TNF provided no benefit or conversely led to increased arthritic changes in the joint tissues.
CONCLUSION:
These results show that intra-articular IL-1, rather than TNF-α, plays a critical role in the acute inflammatory phase of joint injury and can be inhibited locally to reduce post-traumatic arthritis following a closed articular fracture. Targeted local inhibition of IL-1 following joint injury may represent a novel treatment option for PTA.
AuthorsBridgette D Furman, Daniel S Mangiapani, Evan Zeitler, Karsyn N Bailey, Phillip H Horne, Janet L Huebner, Virginia B Kraus, Farshid Guilak, Steven A Olson
JournalArthritis research & therapy (Arthritis Res Ther) Vol. 16 Issue 3 Pg. R134 (Jun 25 2014) ISSN: 1478-6362 [Electronic] England
PMID24964765 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antirheumatic Agents
  • Immunoglobulin G
  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept
Topics
  • Animals
  • Antirheumatic Agents (administration & dosage, blood, pharmacology)
  • Arthritis, Experimental (etiology, metabolism, prevention & control)
  • Etanercept
  • Fractures, Closed (complications)
  • Immunoglobulin G (administration & dosage, blood, pharmacology)
  • Inflammation Mediators (antagonists & inhibitors, metabolism)
  • Injections, Intra-Articular
  • Interleukin 1 Receptor Antagonist Protein (administration & dosage, blood, pharmacology)
  • Interleukin-1 (antagonists & inhibitors, metabolism)
  • Intra-Articular Fractures (complications)
  • Knee Injuries (etiology, metabolism, prevention & control)
  • Knee Joint (drug effects, metabolism, pathology)
  • Male
  • Mice, Inbred C57BL
  • Receptors, Tumor Necrosis Factor (administration & dosage, blood)
  • Synovitis (metabolism, prevention & control)
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)
  • X-Ray Microtomography

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