Acute-phase serum amyloid a in osteoarthritis: regulatory mechanism and proinflammatory properties

PLoS One. 2013 Jun 12;8(6):e66769. doi: 10.1371/journal.pone.0066769. Print 2013.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Reaction / blood*
  • Blotting, Western
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Genistein / pharmacology
  • Humans
  • Interleukin-1beta / pharmacology
  • Joints / metabolism*
  • Lentivirus
  • Osteoarthritis / blood*
  • PPAR gamma / antagonists & inhibitors
  • Rosiglitazone
  • Serum Amyloid A Protein / metabolism*
  • Sulfonamides / pharmacology
  • Synovial Fluid / metabolism
  • Thiazolidinediones / pharmacology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Interleukin-1beta
  • PPAR gamma
  • Serum Amyloid A Protein
  • Sulfonamides
  • TLR4 protein, human
  • Thiazolidinediones
  • Toll-Like Receptor 4
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • Rosiglitazone
  • Genistein

Grants and funding

This study was supported by the "Fond d'Investissement pour la Recherche Scientifique" (FIRS), CHU Liège, Belgium. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.