title: Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors: Bridgette D
authors: BD
authors: Furman
authors: Daniel S
authors: DS
authors: Mangiapani
authors: Evan
authors: E
authors: Zeitler
authors: Karsyn N
authors: KN
authors: Bailey
authors: Phillip H
authors: PH
authors: Horne
authors: Janet L
authors: JL
authors: Huebner
authors: Virginia B
authors: VB
authors: Kraus
authors: Farshid
authors: F
authors: Guilak
authors: Steven A
authors: SA
authors: Olson
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D000068800:Etanercept; D005596:Fractures, Closed / Q000150:complications; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007270:Injections, Intra-Articular; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057072:Intra-Articular Fractures / Q000150:complications; D007718:Knee Injuries / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000097:blood; D013585:Synovitis / Q000378:metabolism / Q000517:prevention & control; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept