title: Inflammatory Cytokines and Matrix Metalloproteinases in the Synovial Fluid After Intra-articular Ankle Fracture.
abstract: BACKGROUND
  Posttraumatic osteoarthritis (PTOA) can occur after intra-articular fracture despite anatomic fracture reduction. It has been hypothesized that an early inflammatory response after intra-articular injury could lead to irreversible cartilage damage that progresses to PTOA. Therefore, in addition to meticulous fracture reduction, it would be ideal to prevent this initial inflammatory response but little is known about the composition of the synovial environment after intra-articular fracture. The purpose of this work was to characterize the inflammatory cytokine and matrix metalloproteinase (MMP) composition in the synovial fluid (SF) of patients with acute intra-articular ankle fractures.
  
  
  METHODS
  Twenty-one patients with an intra-articular ankle fracture were included in this study. All patients had a contralateral ankle joint that was pain free, had no radiographic evidence of arthritis, and no history of trauma. The uninjured ankle served as a matched control. SF was obtained from bilateral ankles at the time of surgery which occurred at a mean of 17 days post-fracture (range 8-40). The SF was analyzed for granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, CTXII, sGAG, and bilirubin/biliverdin (markers of hemearthrosis) using either multiplex assay or ELISA using commercially available kits. Mean concentrations of each factor were compared between SF from fractured and control ankles, and correlation analysis was done to determine potential relationships between levels of cytokines and time from fracture and age at fracture.
  
  
  RESULTS
  Twelve of 18 measured factors including GM-CSF, IL-10, IL-1β, IL-6, IL-8, TNF-α, MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, and bilirubin/biliverdin were found to be significantly higher in the fractured ankles. Mean concentrations of ECM degradation markers (sGAG and CTXII) were not found to be significatnly different between groups.
  
  
  CONCLUSIONS
  These data indicate that after intra-articular ankle fracture the SF exhibits a largely pro-inflammatory and extra-cellular matrix degrading environment similar to that described in idiopathic osteoarthritis. IL-6, IL-8, MMP-1, MMP-2, MMP-3, MMP-9, and MMP-10 were significantly elevated and may play a role in the development of PTOA.
  
  
  CONCLUSIONS
  In addition to anatomic fracture reduction, these data lend credence to reducing acute intra-articular inflammation through the development of antagonists to these pro-inflammatory and degrading mediators. Likewise, intra-articular lavage might reduce this inflammatory burden.
authors.affiliation: Duke University Medical Center, Durham, NC, USA samuel.adams@duke.edu.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Adams
authors.affiliation: Duke University Medical Center, Durham, NC, USA Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Setton
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bell
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Easley
authors.affiliation: Duke University Medical Center, Durham, NC, USA Duke Molecular Physiology Institute, Durham, NC, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Huebner
authors.affiliation: Duke University Medical Center, Durham, NC, USA Duke Molecular Physiology Institute, Durham, NC, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stabler
authors.affiliation: Duke University Medical Center, Durham, NC, USA Duke Molecular Physiology Institute, Durham, NC, USA.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Kraus
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Leimer
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Olson
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Dana L
authors.initials: DL
authors.lastname: Nettles
mesh_terms: D000328:Adult; D016512:Ankle Injuries / Q000378:metabolism* / Q000601:surgery; D016207:Cytokines / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D057072:Intra-Articular Fractures / Q000378:metabolism* / Q000601:surgery; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism; D013582:Synovial Fluid / Q000737:chemistry*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D020782:Matrix Metalloproteinases
keywords: ankle fracture; arthritis; interleukin; intra-articular; joint injury; matrix metalloproteinase; osteoarthritis; posttraumatic; synovial fluid