title: Do changing toll-like receptor profiles in different layers and grades of osteoarthritis cartilage reflect disease severity?
abstract: OBJECTIVE
  Cartilage degeneration in osteoarthritis (OA) leads to release of potential danger signals. The aim of our study was to profile OA cartilage for the Toll-like receptor (TLR) danger signal receptors.
  
  
  METHODS
  Osteochondral cylinders from total knee replacements were graded using OA Research Society International score and stained for proteoglycans, collagenase-cleaved type II collagen, and TLR 1-10, which were analyzed histomorphometrically.
  
  
  RESULTS
  Grade 1 OA lesions contained 22%-55% TLR 1-9-positive cells in the surface zone, depending on the TLR type. In Grade 2 TLR, immunoreactivity was 60%-100% (p < 0.01) and it was even higher in Grades 3 and 4 (p < 0.01 vs Grade 1). TLR-positive cells in Grade 1 middle zone were low, 0-19.9%, but were 5.1%-32.7% in Grade 2 (p < 0.01) and 34%-83% in Grades 3-4 samples (p < 0.001). TLR values in Grade 5 were low (14.3%-28.7%; p < 0.001). In Grades 3-4 OA, cartilage matrix stained strongly for TLR. In Grade 1, COL2-3/4M was restricted to chondrocytes, but was increasingly seen in matrix upon progress of OA to Grade 4, and then declined.
  
  
  CONCLUSIONS
  Cells in the gliding surface zone are fully equipped with TLR in mild OA. Their proportion increases and extends to the middle or even the deep zone, reflecting OA progression. COL2A-3/4M staining suggests Endo180-mediated intake for intralysosomal degradation by cathepsins in Grade 1, but in higher grades this chondrocyte-mediated clearance fails and the matrix demonstrates extensive collagenase-induced damage. Detached and/or partially degraded matrix components can then act as endogenous danger signals (damage-associated molecular patterns or DAMP) and stimulate increasingly TLR-equipped chondrocytes to inflammation. At the peak inflammatory response, soluble TLR may exert negative feedback, explaining in part the low TLR levels in Grade 5 OA.
authors.affiliation: Department of Medicine, University of Helsinki/Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Barreto
authors.forename: Tarvo
authors.initials: T
authors.lastname: Sillat
authors.forename: Antti
authors.initials: A
authors.lastname: Soininen
authors.forename: Pekka
authors.initials: P
authors.lastname: Ylinen
authors.forename: Abdelhakim
authors.initials: A
authors.lastname: Salem
authors.forename: Yrjö T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Samadi
authors.forename: Dan C E
authors.initials: DC
authors.lastname: Nordström
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007719:Knee Joint / Q000473:pathology / Q000601:surgery; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D051193:Toll-Like Receptors
keywords: CARTILAGE; CHONDROCYTES; IMMUNOHISTOCHEMISTRY; OSTEOARTHRITIS