Physiological concentrations of soluble uric acid are chondroprotective and anti-inflammatory

Jenn-Haung Lai,Shiu-Bii Lien,Chuan-Yueh Huang,B Linju Yen,Shue-Fen Luo,Li-Feng Hung,Leou-Chyr Lin,Feng-Cheng Liu,Ling-Jun Ho

doi:10.1038/s41598-017-02640-0

Abstract

High uric acid levels are a risk factor for cardiovascular disorders and gout; however, the role of physiological concentrations of soluble uric acid (sUA) is poorly understood. This study aimed to clarify the effects of sUA in joint inflammation. Both cell cultures of primary porcine chondrocytes and mice with collagen-induced arthritis (CIA) were examined. We showed that sUA inhibited TNF-α- and interleukin (IL)-1β–induced inducible nitric oxide synthase, cyclooxygenase-2 and matrix metalloproteinase (MMP)-13 expression. Examination of the mRNA expression of several MMPs and aggrecanases confirmed that sUA exerts chondroprotective effects by inhibiting the activity of many chondro-destructive enzymes. These effects attenuated collagen II loss in chondrocytes and reduced proteoglycan degradation in cartilage explants. These results were reproduced in chondrocytes cultured in three-dimensional (3-D) alginate beads. Molecular studies revealed that sUA inhibited the ERK/AP-1 signalling pathway, but not the IκBα-NF-κB signalling pathway. Increases in plasma uric acid levels facilitated by the provision of oxonic acid, a uricase inhibitor, to CIA mice exerted both anti-inflammatory and arthroprotective effects in these animals, as demonstrated by their arthritis severity scores and immunohistochemical analysis results. Our study demonstrated that physiological concentrations of sUA displayed anti-inflammatory and chondroprotective effects both in vitro and in vivo.

Highlights

Cartilage is one of the major components of synovial joints and facilitates load transfer and joint movement
We investigated the protective effects of several physiological concentrations of soluble uric acid (sUA) on chondrocyte/cartilage degradation induced by inflammation
The results showed that IL-1β and TNF-α induced inducible nitric oxide synthase, cyclooxygenase-2 (COX2), and pro–matrix metalloproteinase (MMP)-13 expression in the chondrocytes, and that these effects were suppressed by sUA (Fig. 1)

Summary

Introduction

Cartilage is one of the major components of synovial joints and facilitates load transfer and joint movement. Uric acid was shown to regulate the inflammatory response in damaged tissues in a mouse model of liver injury[10]. Uric acid-lowering therapy was shown to exert beneficial effects in patients with cardiovascular diseases[12]. A recent study showed that administering allopurinol to heart failure patients treated with atorvastatin to reduce serum uric acid levels did not provide beneficial effects in these patients[13]. In contrast to studies showing that elevated serum uric acid levels potentially increase the risk of cardiovascular disease, an early study suggested that uric acid may have antioxidant effects[14]. Given that uric acid plays a complex role in the inflammatory response, in the present study, we investigated the possible pro- or anti-inflammatory effects of physiological concentrations (15–60 μg/ml) of soluble uric acid (sUA) in joint disease. The results of the study indicate that sUA exerts both anti-inflammatory and chondroprotective effects in vitro and in vivo

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Conclusion