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

Arthritis Res Ther. 2014 Jun 25;16(3):R134. doi: 10.1186/ar4591.


Introduction: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / blood
  • Antirheumatic Agents / pharmacology
  • Arthritis, Experimental / etiology
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / prevention & control
  • Etanercept
  • Fractures, Closed / complications
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / blood
  • Immunoglobulin G / pharmacology
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Injections, Intra-Articular
  • Interleukin 1 Receptor Antagonist Protein / administration & dosage
  • Interleukin 1 Receptor Antagonist Protein / blood
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / metabolism*
  • Intra-Articular Fractures / complications
  • Knee Injuries / etiology
  • Knee Injuries / metabolism*
  • Knee Injuries / prevention & control
  • Knee Joint / drug effects
  • Knee Joint / metabolism*
  • Knee Joint / pathology
  • Male
  • Mice, Inbred C57BL
  • Receptors, Tumor Necrosis Factor / administration & dosage
  • Receptors, Tumor Necrosis Factor / blood
  • Synovitis / metabolism
  • Synovitis / prevention & control
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*
  • X-Ray Microtomography


  • Antirheumatic Agents
  • Immunoglobulin G
  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept