title: Acute-phase serum amyloid a in osteoarthritis: regulatory mechanism and proinflammatory properties.
abstract: OBJECTIVE
  To determine if serum amyloid A (A-SAA) could be detected in human osteoarthritic (OA) joints and further clarify if high A-SAA level in joints result from a local production or from a diffusion process from abnormally elevated plasma concentration. Regulatory mechanism of A-SAA expression and its pro-inflammatory properties were also investigated.
  
  
  METHODS
  A-SAA levels in serum and synovial fluid of OA (n = 29) and rheumatoid arthritis (RA) (n = 27) patients were measured and compared to matched-healthy volunteers (HV) (n = 35). In vitro cell cultures were performed on primary joint cells provided from osteoarthritis patients. Regulatory mechanisms were studied using Western-blotting, ELISA and lentiviral transfections.
  
  
  RESULTS
  A-SAA was statistically increased in OA plasma patients compared to HV. Moreover, A-SAA level in OA plasma and synovial fluid increased with the Kellgren & Lauwrence grade. For all OA and RA patients, A-SAA plasma level was higher and highly correlated with its corresponding level in the synovial fluid, therefore supporting that A-SAA was mainly due to the passive diffusion process from blood into the joint cavity. However, A-SAA expression was also observed in vitro under corticosteroid treatment and/or under IL-1beta stimuli. A-SAA expression was down-regulated by PPAR-γ agonists (genistein and rosiglitazone) and up-regulated by TGF-β1 through Alk1 (Smad1/5) pathway. RhSAA induced proinflammatory cytokines (IL-6, IL-8, GRO-α and MCP-1) and metalloproteinases (MMP-1, MMP-3 and MMP-13) expression in FLS and chondrocytes, which expression was downregulated by TAK242, a specific TLR4 inhibitor.
  
  
  CONCLUSIONS
  Systemic or local A-SAA expression inside OA joint cavity may play a key role in inflammatory process seen in osteoarthritis, which could be counteracted by TLR4 inhibition.
authors.affiliation: Laboratory of Rheumatology, GIGA Research, University of Liège, CHU Liège, Liège, Belgium. ddeseny@chu.ulg.ac.be
authors.forename: Dominique
authors.initials: D
authors.lastname: de Seny
authors.forename: Gaël
authors.initials: G
authors.lastname: Cobraiville
authors.forename: Edith
authors.initials: E
authors.lastname: Charlier
authors.forename: Sophie
authors.initials: S
authors.lastname: Neuville
authors.forename: Nathalie
authors.initials: N
authors.lastname: Esser
authors.forename: Denis
authors.initials: D
authors.lastname: Malaise
authors.forename: Olivier
authors.initials: O
authors.lastname: Malaise
authors.forename: Florence Quesada
authors.initials: FQ
authors.lastname: Calvo
authors.forename: Biserka
authors.initials: B
authors.lastname: Relic
authors.forename: Michel G
authors.initials: MG
authors.lastname: Malaise
mesh_terms: D000210:Acute-Phase Reaction / Q000097:blood*; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007596:Joints / Q000378:metabolism*; D016086:Lentivirus; D010003:Osteoarthritis / Q000097:blood*; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D000077154:Rosiglitazone; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013582:Synovial Fluid / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D047495:PPAR gamma; D000685:Serum Amyloid A Protein; D013449:Sulfonamides; C495345:TLR4 protein, human; D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D000077154:Rosiglitazone; D019833:Genistein