Acute-Phase Serum Amyloid A in Osteoarthritis: Regulatory Mechanism and Proinflammatory Properties

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.

Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells

“…2A). We could confirm that rhSAA1 induces its own endogenous expression (SAA1 and SAA2) as well as the expression of IL1B, IL6, IL8 and CXCL1, as described in osteoarthritic fibroblast-like synoviocytes (de Seny et al, 2013). IL-6 and IL-8 secretion could also been quantified after rhSAA1 stimulation by ELISA in 3 different hMSC donors (Fig.…”

“…Serum amyloid protein is another stimulator of inflammation that is secreted by the liver in large amounts in response to injury and infection. However it can also be locally produced in diseases such as rheumatoid arthritis, osteoarthritis and atherosclerosis (Kovacevic et al, 2008;Vallon et al, 2001;de Seny et al, 2013;Meek et al, 1994;Eklund et al, 2012). TLR2 and TLR4 have been shown to be functional receptors for SAA (Cheng et al, 2008;Sandri et al, 2008).…”

“…Serum amyloid A proteins 1 and 2 (SAA1 and 2) are the major acutephase proteins systemically secreted by the liver in response to inflammation, trauma or infection but local expression was also detected in various other tissues such as the bone, cartilage and vessels, as well as in inflamed tissues and serum in osteoarthritis and atherosclerosis (Kovacevic et al, 2008;Vallon et al, 2001;de Seny et al, 2013;Meek et al, 1994;Eklund et al, 2012). SAA proteins are encoded by the SAA1 and SAA2 genes, which seem to be coordinately expressed (Thorn et al, 2004).…”

“…In turn autocrine SAA was described to amplify the proinflammatory environment by again stimulating cytokine expression, e.g. IL6, IL8, and CXCL1, and to induce the expression of metalloproteinases at the tissue level (Vallon et al, 2001;de Seny et al, 2013). The signal transduction pathways SAA proteins can address are transmitted via TLR2 and 4 receptors and via the formyl peptide receptor FPRL1 in various cell systems (Cheng et al, 2008;Sandri et al, 2008;Dong et al, 2011;Su et al, 1999).…”

Ascorbic acid provides protection for human chondrocytes against oxidative stress

“…Several response transcription factors and signaling pathways, including MMP-3 (39), NF-κ B (13), the PKC/Nrf2 pathway (40) and the JNK/AP1 signaling pathway (41,42), have been demonstrated to exert key effects on the protection against environmental and multiple cellular stresses in chondrocytes (13,(39)(40)(41)(42). Theoretically, the specific regulation of these response transcription factors can cause various changes in pathologies and physiologies.…”