Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Lubricin/proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblast and superficial zone chondrocyte. PRG4 has a homeostatic multifaceted role in the joint including boundary lubrication, friction lowering of apposed cartilage surfaces and prevention of synovial overgrowth. PRG4 is abundant in the synovial fluid (SF) and its levels are reduced in SF from patients with inflammatory arthropathies3. In animal models of post-traumatic osteoarthritis (OA) and inflammatory arthritis, PRG4 expression is reduced in cartilage and synovium. PRG4 intra-articular treatment retards progression of cartilage degeneration in preclinical post-traumatic osteoarthritis. Recent studies have suggested that PRG4 may have anti-inflammatory properties. Musculoskeletal ultrasound studies have highlighted the deposition of MSU-crystals onto the superficial margin of cartilage defined by US OMERACT definition as the Òdouble contourÓ sign and its deposition contributes to abnormal joint homeostasis. The objective of this study was to evaluate the anti-inflammatory properties of PRG4 in MSU in acute gout inflammation
Methods: Synovial fluid (SF) aspirates from normal and patients with acute gout flares were used to evaluate the activation TLR2 and TLR4 on HEK cells. Activation of TLR2 and TLR4 on HEK cells was assessed by immunoprecipitation of PRG4 from gout SF. We evaluated the impact of recombinant human PRG4 (rhPRG4) on MSU-induced release of interleukin-1 beta (IL-1b), tumor necrosis factor alpha (TNF-a), interleukin-8 (IL-8) by human monocytic cell line, THP-1 using ELISA, immunohistochemistry, and western-blot analysis. We also evaluated the role rhPRG4 in inhibiting the NLRP3 inflammasome in THP-1 cells.
Results: Using TLR-HEK cells systems, we found that synovial fluid from acute gout (n=5) activated primarily through TLR2 rather than TLR4. Normal synovial fluid did not result in either TLR2 and TLR4 activation. Gout SF treatment resulted in a significant higher TLR2 activation compared to normal SF (p<0.001). Removal of PRG4 from gout SF by immunoprecipitation with a monoclonal anti-PRG4 antibody resulted in higher TLR2-HEK activation compared to gout SF and untreated controls. In a dose dependent manner, rhPRG4 significantly inhibited IL-1b, TNF-a and IL-8 production by human monocytic cell line, THP-1 in response to MSU using ELISA, western blot analysis and immunohistochemistry. Immunohistochemistry of NLRP3 showed a dose dependent inhibition by rhPRG4 comparable to its inhibition by colchicine.
Conclusion: PRG4 is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes which retards progression MSU-crystal induced arthritis by binding to TLR2 and this binding mediates a novel anti-inflammatory role for PRG4 in joint homeostasis. Our findings provide a better understanding of the molecular mechanism(s) of PRG4 in MSU-crystal induced arthritis with important implications in the development of novel biological strategies in gout.
To cite this abstract in AMA style:Reginato AM, Qadri M, Sun C, Schmidt T, Yang N, Elsaid K, Jay G. Anti-Inflammatory Role of Lubricin/Proteoglycan 4 (PRG4) in Monosodium Urate (MSU)-Crystal Induced Arthritis. [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/anti-inflammatory-role-of-lubricinproteoglycan-4-prg4-in-monosodium-urate-msu-crystal-induced-arthritis/. Accessed November 27, 2020.
« Back to 2016 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-inflammatory-role-of-lubricinproteoglycan-4-prg4-in-monosodium-urate-msu-crystal-induced-arthritis/