Acute-Phase Serum Amyloid A Regulates Tumor Necrosis Factor alpha and Matrix Turnover and Predicts Disease Progression in Patients With Inflammatory Arthritis Before and After Biologic Therapy

St. Vincent's University Hospital, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.
Arthritis & Rheumatology (Impact Factor: 7.76). 04/2012; 64(4):1035-45. DOI: 10.1002/art.33455
Source: PubMed


To investigate the relationship between acute-phase serum amyloid A (A-SAA) and joint destruction in inflammatory arthritis.
Serum A-SAA and C-reactive protein (CRP) levels, the erythrocyte sedimentation rate (ESR), and levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-9, MMP-13, tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), and type I and type II collagen–generated biomarkers C2C and C1,2C were measured at 0–3 months in patients with inflammatory arthritis commencing anti–tumor necrosis factor α (anti-TNFα) therapy and were correlated with 1-year radiographic progression. The effects of A-SAA on MMP/TIMP expression on RA fibroblast-like synoviocytes (FLS), primary human chondrocytes, and RA/psoriatic arthritis synovial explant cultures were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, antibody protein arrays, and gelatin zymography.
Serum A-SAA levels were significantly (P < 0.05) correlated with MMP-3, the MMP-3:TIMP-1 ratio, C1,2C, C2C, and VEGF. The baseline A-SAA level but not the ESR or the CRP level correlated with the 28-joint swollen joint count and was independently associated with 1-year radiographic progression (P = 0.038). A-SAA increased MMP-1, MMP-3, MMP-13, and MMP/TIMP expression in RA FLS and synovial explants (P < 0.05). In chondrocytes, A-SAA induced MMP-1, MMP-3, and MMP-13 messenger RNA and protein expression (all P < 0.01), resulting in a significant shift in MMP:TIMP ratios (P < 0.05). Gelatin zymography revealed that A-SAA induced MMP-2 and MMP-9 activity. Blockade of the A-SAA receptor SR-B1 (A-SAA receptor scavenger receptor-class B type 1) inhibited MMP-3, MMP-2, and MMP-9 expression in synovial explant cultures ex vivo. Importantly, we demonstrated that A-SAA has the ability to induce TNFα expression in RA synovial explant cultures (P < 0.05).
A-SAA may be involved in joint destruction though MMP induction and collagen cleavage in vivo. The ability of A-SAA to regulate TNFα suggests that A-SAA signaling pathways may provide new therapeutic strategies for the treatment of inflammatory arthritis.

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Available from: Robin Poole, Sep 23, 2014
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    • "Its concentration may increase up to 1000-fold during the acute phase of inflammation in regard to normal condition [10], [11]. Besides its influence on lipid metabolism [12], [13], A-SAA is known to participate to immune cells recruitment at inflammatory sites [14], [15] and to induce expression of pro-inflammatory cytokines [14], [16] and matrix metalloproteinases [17]. Across the last decade, several studies attempted to demonstrate the extra-hepatic production of A-SAA by several tissues and different cell types of patients with atherosclerosis [18], Alzheimer disease [19], obesity [9] or RA [20], [21]. "
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    ABSTRACT: 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. 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. 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. 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.
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    • "IL-1β, IL-6, IL-8, TNF-α, and interferon-γ) in neutrophils [19], [20], monocytes [15], [21] and lymphocytes [22], and is a leukocyte chemoattractant [23], [24]. Several receptors are implicated, including the receptor for advanced glycation end products (RAGE) [16], [25], formyl peptide receptor-like (FPRL)-1 and -2 [20], [26]–[29], toll-like receptor (TLR)-2 and -4 [30]–[32], and scavenger receptors CLA-1/SR-B1 [33]–[35] and CD36 [36] that modulate innate immune responses to several ligands. Recent studies suggest that in macrophages, four signaling pathways involving nuclear factor-κB (NF-κB) and three mitogen-activated protein kinase (MAPK) may contribute to cytokine production (summarized in [36]). "
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    • "SAA augments the inflammatory response in a cytokine-like fashion by attracting monocytes/macrophages, leukocytes and T lymphocytes, while promoting neutrophil survival and endothelial activation and stimulating the production of the proinflammatory mediators TNF, IL-1, IL-6, IL-8, and IL-17, thus initiating an amplifying loop. Exposure of synovial fibroblasts and chondrocytes to SAA promotes MMP-3 mediated adhesion molecule expression, as well as phagocytosis and chemotaxis of monocytes and neutrophils, thereby contributing to synovial inflammation, hyperplasia, angiogenesis, and joint destruction [9]. SAA has also been implicated in the pathogenesis of atherosclerosis and premature cardiovascular disease, an important aspect in the management of patients with RA, thus making it a potential target for therapy to control both RA and its complications. "
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