Abstract
ObjectiveTo 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.MethodsA-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.ResultsA-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.ConclusionSystemic 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.
Highlights
Osteoarthritis (OA) is a degenerative disorder characterized by a progressive cartilage breakdown, osteophyte formation, subchondral bone thickening and local inflammatory process
A-SAA levels in plasma and synovial fluid Plasma A-SAA (Figure 1A) levels were significantly higher in the OA than in the healthy volunteers (HV) group and remained lower in the OA than in the rheumatoid arthritis (RA) group
For all OA and RA patients, A-SAA plasma level was higher compared to its corresponding level in the synovial fluid in a range of 3 to 44 fold
Summary
Osteoarthritis (OA) is a degenerative disorder characterized by a progressive cartilage breakdown, osteophyte formation, subchondral bone thickening and local inflammatory process. It is considered as a metabolic disorder since mechanical stress alone cannot explain the link between obesity and pathology in non-weight-bearing joints, such as hand OA [1,2,3,4]. Recent evidences suggest that chondrocytes can under physiological and pathological conditions synthesize several non-matrix factors like adipokines that contribute to cartilage degradation within articular joints [5]. FLS are able to secrete adipokines such as leptin [7]. A-SAA (SAA1 and SAA2, collectively called A-SAA) has been recently placed on the front stage of research for its convergence to both inflammation and metabolic pathways [8,9]
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