Lubricin/CD44/PP2A Pathway Offers New Therapeutic Targets for Patients with Gout

Moreover, in a different study using the same model, the PP2A activator decreased neutrophil infiltration and infiltration of pro-inflammatory type, classical monocytes, while increasing infiltration of anti-inflammatory non-classical monocytes.⁶

“So we were able to show that the intracellular modulator PP2A does play a role in the degree of response in urate crystal inflammation,” said Dr. Elsaid.

Lubricin in Gout Pathophysiology

Dr. Elsaid and colleagues also studied urate crystal inflammation using recombinant human lubricin (rh-lubricin) using in vitro and in vivo models. They demonstrated a reduction in MSU crystal phagocytosis as well as decreased IL‐1β and IL-8 release compared with controls.⁷

They also examined the inflammasome in human macrophages, demonstrating that rh-lubricin resulted in decreased expression of inflammasome proteins, of IL‐1β and of caspase-1, a response that was specific to uric acid crystals.⁷

“Being a major component in synovial fluid, [lubricin] may play a role in terms of uric crystal aggregation and formation,” said Dr. Elsaid. To follow up on this idea, they applied rh-lubricin to bone marrow-derived macrophages, which reduced the activity of xanthine oxidase and of cellular uric acid. Moreover, they were able to reduce MSU crystal formation with increasing amounts of rh-lubricin.⁸

“Uric acid crystal uptake by synovial macrophages is the upstream hallmark for the gout pathophysiology,” concluded Dr. Elsaid. “That full circuit [of lubricin/CD44/PP2A] is an emerging multi-targeted pathway in gout pharmacology.”

Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.

References

1. Elsaid KA, Jay, Liu-Bryan GD, Terkeltaub R. Proteoglycan 4 (PRG4)/lubricin and

   the extracellular matrix in gout. Gout Urate Crys Depos Dis. 2023;1:122–136.

2. Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet. 2021;397(10287):1843–1855.
3. James R, Paul BJ. New and emerging therapies in gout. Rheumatology and Autoimmunity. 2023;3:70–77.
4. Bousoik E, Qadri M, Elsaid KA. CD44 receptor mediates urate crystal phagocytosis by macrophages and regulates inflammation in a murine peritoneal model of acute gout. Sci Rep. 2020;10(1):5748.
5. Qadri M, Almadani S, Jay GD, Elsaid KA. Role of CD44 in Regulating TLR2 activation of human macrophages and downstream expression of proinflammatory cytokines. J Immunol. 2018 Jan 15;200(2):758–767. 
6. Elsayed S, Elsaid KA. Protein phosphatase 2A regulates xanthine oxidase-derived ROS production in macrophages and influx of inflammatory monocytes in a murine gout model. Front Pharmacol. 2022;13:1033520. 
7. Qadri M, Jay GD, Zhang LX, et al. Recombinant human proteoglycan-4 reduces phagocytosis of urate crystals and downstream nuclear factor kappa B and inflammasome activation and production of cytokines and chemokines in human and murine macrophages. Arthritis Res Ther. 2018;20(1):192.
8. Elsaid K, Merriman TR, Rossitto LA, et al. Amplification of inflammation by lubricin deficiency implicated in incident, erosive gout independent of hyperuricemia. Arthritis Rheumatol. 2023;75(5):794–805.