Does hyperuricemia correlate with intervertebral disc degeneration?

Does hyperuricemia correlate with intervertebral disc degeneration?

Journal Pre-proofs Does hyperuricemia correlate with intervertebral disc degeneration? Yvang Chang, Ming Yang, Yu Zhang, Gang Xu, Zhonghai Li PII: DOI...

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Journal Pre-proofs Does hyperuricemia correlate with intervertebral disc degeneration? Yvang Chang, Ming Yang, Yu Zhang, Gang Xu, Zhonghai Li PII: DOI: Reference:

S0306-9877(20)30303-0 https://doi.org/10.1016/j.mehy.2020.109673 YMEHY 109673

To appear in:

Medical Hypotheses

Received Date: Accepted Date:

26 February 2020 10 March 2020

Please cite this article as: Y. Chang, M. Yang, Y. Zhang, G. Xu, Z. Li, Does hyperuricemia correlate with intervertebral disc degeneration?, Medical Hypotheses (2020), doi: https://doi.org/10.1016/j.mehy.2020.109673

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© 2020 Published by Elsevier Ltd.

Does hyperuricemia correlate with intervertebral disc degeneration?

Yvang Chang1,2, Ming Yang1,2, Yu Zhang1,2, Gang Xu1,2, Zhonghai Li1,2*

1

Department of Orthopaedics, First Affiliated Hospital of Dalian Medical University,

Dalian, the People’s Republic of China 2

Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopaedic

Diseases, Liaoning Province, the People’s Republic of China

* Corresponding

Author: Zhonghai Li MD

Tel: 86-18098876419

Fax: 86-411-83635963 E-mail: [email protected]

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Summary: Gout is a form of crystal arthropathy associated with deposition of monosodium urate (MSU) crystals, and is directly related to hyperuricemia arising from abnormal purine metabolism and/or decreased uric acid excretion. Uric acid is the final oxidation product of purine metabolism and plays an important role as an in vivo antioxidant at physiological concentrations. Several case reports have described the presence of tophi in the intervertebral disc (IVD) or endplate of patients with hyperuricemia or gout, and these patients also exhibited severe intervertebral disc degeneration (IDD). We speculated that uric acid may have dual effects on an IVD. On the one hand, physiological concentrations of uric acid have powerful antioxidant activity and can effectively maintain the steady state of the IVD, while on the other hand, high concentrations of uric acid have strong oxidizing activity and the resulting high osmotic pressure can aggravate IDD. Moreover, when MSU crystals accumulate in the endplate and IVD, they lead to a series of mechanical damages and inflammatory reactions that further accelerate IDD. Further basic and clinical studies are needed to clarify the mechanism for the involvement of uric acid in the onset and development of IDD.

Keywords: Intervertebral disc (IVD); Intervertebral disc degeneration (IDD); Gout; Uric acid

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Background Uric acid is the end product of purine metabolism. Endogenous uric acid accounts for 80% of the total uric acid and is derived from the decomposition of nucleic acids, while exogenous uric acid is generated from the metabolism of dietary purines and accounts for about 20% of the total uric acid. The normal body uric acid pool stores about 1200 mg of uric acid. Approximately 700 mg of uric acid is produced daily, of which about two-thirds is excreted through the kidney, about one-third through the intestinal tract, and very small amounts through the sweat glands. Under physiological conditions, production and excretion of uric acid in the human body are essentially maintained in a dynamic balance. However, under conditions such as deficiency of enzymes involved in purine metabolism, excessive intake of exogenous purine, or decreased uric acid excretion through the kidney, the concentration of serum uric acid increases. Hyperuricemia is diagnosed when the serum uric acid level exceeds 420 μmol/L in males and postmenopausal females, or 360 μmol/L in non-menopausal females [1]. Hyperuricemia is mainly classified into three types according to the underlying cause: uric acid overproduction type, uric acid underexcretion type, and combined type. When the increase in serum uric acid leads to the formation of monosodium urate (MSU) crystals, their deposition in and around synovial joints triggers severe pain through local inflammatory reactions in the joints, which is termed gout. MSU crystals show strong negative birefringence under polarized light, which is the gold standard for gout diagnosis [2]. MSU crystals are more likely to form at lower temperatures, and thus gout typically affects peripheral joints like the first metatarsophalangeal joint, ankle, knee, and elbow [3]. Epidemiological studies have revealed that the global prevalence of gout is increasing. In an epidemiological survey in the United States [4], the prevalence of gout in adults from 2015 to 2016 was 3.9% (9.2 million), comprising 5.2% (5.9 million) males and 2.7% (3.3 million) females. The mean uric acid level in males and females was 6.0 and 4.8 mg/dl, and the prevalence of hyperuricemia was 20.2% and 20.0%, respectively. Furthermore, gout mainly affected the population aged >40 years and had stronger effects on males than on females. In another study, gout less commonly involved the spine, but when the spine was involved, the lumbar vertebrae were usually affected, followed by the cervical vertebrae and thoracic vertebrae [5]. Spinal gout was also reported to involve the spinal facet joint, lamina, and ligamentum flavum [6], and its 3

clinical manifestations mainly included myelopathy, nerve root disorder, and intervertebral disc (IVD) inflammation, with fever, local pain, and osteolytic lesions in some cases [7-9]. During the process of intervertebral disc degeneration (IDD), the extracellular matrix (ECM) of the IVD decreased, type II collagen decreased, type I collagen increased, proteoglycan expression decreased significantly, and degradative enzyme expression was up-regulated [10], mainly comprising matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs). In addition, inflammatory factors like nitric oxide (NO) can cause stress-induced premature senescence (SIPS), which further induces apoptosis [11]. Nerve and vascular ingrowth into the IVD is also considered to be one of the pathogeneses for IDD. Some researchers found that polyproteoglycans in the normal IVD ECM inhibited this nerve ingrowth and vascular endothelial growth, suggesting that a decreased polyproteoglycan content in the IDD may one of the mechanisms for the nerve and vascular ingrowth in IDD [12]. In this study, the potential role of different concentrations of serum uric acid in the pathogenesis of IDD was analyzed.

The hypothesis Reactive oxygen species (ROS) are closely associated with the onset and progress of IDD [13]. We speculated that physiological concentrations of uric acid play an important role in maintenance of IVD homeostasis, through their strong antioxidant activity by removing ROS from the IVD. However, the hyperosmotic environment caused by high concentrations of uric acid can lead to DNA damage in nucleus pulposus cells. In addition, the strong oxidizing activity of high concentrations of uric acid can affect aerobic metabolism in the IVD. Furthermore, the formation of MSU crystals can destroy the cartilage endplate and affect the transport of nutrients, while accumulation of MSU crystals in the IVD can cause mechanical damage in the IVD, resulting in acute or chronic IVD inflammation. These changes may play an important role in IDD. Effect of the antioxidant activity of physiological concentrations of serum uric acid on IDD Several studies have shown that oxidative damage increases with age in various tissues and organisms [14]. Endogenous ROS are byproducts of normal oxygen metabolism and cellular responses to pro-inflammatory cytokines [15]. Mitochondria are the major producers of ROS in 4

non-immune cells. Although IVD cells exist in anoxic environments, the cells in normal intact IVD tissues are not completely anaerobic and still undergo oxidative metabolism. With increasing age, the structure of the IVD is gradually destroyed with accumulation of cracks, resulting in neovascularization and exposure of anoxic resident cells to higher oxygen pressure [16]. IVD damage can also cause inflammation and drive ROS production. Furthermore, ROS can act on ECM proteins in the IVD, cause oxidative damage to the ECM of the IVD, damage the mechanical function of the IVD, and accelerate the process of IDD. Supplementation of antioxidants can inhibit the production of ROS in IVD cells, thereby promoting matrix synthesis by IVD cells and preventing IVD cell death and senescence [17]. Multiple studies have proven that extracellular uric acid at physiological concentrations is a strong antioxidant that can reduce the negative effects of oxidative stress by participating in the formation of hydrogen peroxide and scavenging ROS. Specifically, it can scavenge about 60% of body ROS, including reactive oxygen, reactive nitrogen, peroxynitrate, hydroxyl groups, and singlet oxygen[18]. It has been confirmed that a decrease in ROS can significantly affect the level of autophagy in the IVD, and that oxidative stress can induce apoptosis of nucleus pulposus cells through the mitochondrial apoptosis pathway [19]. Meanwhile, oxidative stress can induce autophagy of nucleus pulposus cells by activating the extracellular-regulated protein kinase (ERK) signaling pathway, and inhibition of autophagy can reduce apoptosis induced by oxidative stress and maintain the stability of the IVD structure [20]. Therefore, we assumed that physiological concentrations of serum uric acid play an important role in maintaining the oxidative stress balance in the IVD, thereby effectively maintaining the steady state of the IVD and delaying IDD. Oxidizing activity of high concentrations of serum uric acid and effect of the hyperosmotic state on IDD High concentrations of serum uric acid exert oxidation-promoting effects, such as oxidization of low-density lipoprotein in the presence of copper and lipid peroxide [21]. High concentrations of uric acid can also induce oxidative stress in the liver, accumulation of triglyceride, and dysfunction of mitochondria [22]. Furthermore, animal experiments revealed that high concentrations of uric acid can cause oxidative stress in mitochondria and activate the autophagy pathway, resulting in apoptosis of renal tubular epithelial cells [23]. High concentrations of serum uric acid can also induce oxidative damage in cardiomyocytes and inhibit cardiomyocyte activity 5

by activating the ERK/p38 signaling pathway [24]. Xanthine oxidase (XO) plays an important role in the formation of uric acid, and can also oxidize nicotine adenine dinucleotides under certain conditions, thereby inducing ROS production [25]. Therefore, we assumed that high concentrations of serum uric acid can induce ROS production in the IVD, which in turn promotes oxidative stress in the IVD and aggravates IDD. A previous study showed that a hyperosmotic state can reduce the proliferation potential of nucleus pulposus cells by delaying the G2/M and G0/G1 phases of the cell cycle in vitro [26]. Another study confirmed that an extracellular hyperosmotic state in vitro can change the cell volume, leading to increases in intracellular ion concentrations and resulting in DNA damage in nucleus pulposus cells [27]. A hyperosmotic state can inhibit DNA synthesis mediated by PDGF or IGF-I in nucleus pulposus cells, thus aggravating IDD [28]. We speculated that, in addition to strong oxidizing activity, the high osmotic pressure induced by high concentrations of serum uric acid plays an important role in IDD. Effects of MSU crystals on IDD During purine metabolism in the body, the formation and excretion of serum uric acid are in a dynamic balance. In the presence of excessive production of serum uric acid, insufficient excretion of serum uric acid, or coexistence of these two factors, the dynamic balance is broken, resulting in excessive blood uric acid in the body. Furthermore, MSU crystals form when the concentration of uric acid exceeds its solubility, leading to typical accumulation of white sand-like crystals around the synovial joints. A case report described accumulation of MSU crystals in the IVD, and endplate manifestations such as chisel-like vertebral endplate destruction accompanied by sclerosis [29]. During an acute gout attack, MSU crystals can stimulate and cause edema, congestion, inflammatory reactions, and even bone destruction in the surrounding tissues. MSU crystals can cause injury to cells and mediate inflammatory responses, including phagocytosis of macrophages and production of inflammatory factors like prostaglandin, bradykinin, IL-1, IL-6, and TNF-α [30]. MSU crystals will continue to accumulate until the imbalance is repaired [6]. The cartilage endplate is a horizontal layer of hyaluronic cartilage that forms an important morphological and functional connection between the IVD and the vertebral body. In the normal adult IVD, the blood supply is limited to a few millimeters of the external fiber ring [31]. This unique structure enables IVD transport of nutrients and oxygen through the cartilage endplate, and 6

the vascular network in the vertebral endplate functions as a channel for the diffusion of nutrients and oxygen to the IVD. MSU crystal accumulation in the endplate causes inflammation and bone destruction in the endplate, thereby affecting the supply of nutrients and oxygen to the IVD through the cartilage endplate [32]. A low pH environment facilitates the crystallization of MSU [33]. Although IVD cells mainly undertake anoxic metabolism, a small amount of aerobic metabolism still exists and a decrease in oxygen will thus lead to a decrease in pH [34]. Therefore, we speculated that a low pH internal environment in the IVD facilitates the crystallization of MSU, which in turn affects the nutrient supply of the IVD and aggravates IDD. The ECM of the IVD contains a variety of proteoglycans. These proteoglycan molecules are huge and possess many negative charges. Consequently, the anion gap caused by proteoglycans can significantly increase the solubility of MSU and thus prevent its crystallization [16]. MSU crystals can cause injury to cells and induce the release of inflammatory factors [30]. We speculated that the structure of proteoglycans can be destroyed by the mechanical damage caused by MSU crystals, while the increased expression of proteases mediated by inflammatory factors can lead to the degradation of proteoglycans in the ECM of the IVD, resulting in further decreases in MSU solubility and the precipitation of more crystals. The above process will lead to further destruction of the IVD structure, such as degeneration of the nucleus pulposus and rupture of the annulus fibrosus.

Consequences of the hypothesis Uric acid may play dual roles in the IVD. On the one hand, physiological concentrations of uric acid have strong antioxidant activity and maintain the steady state in the IVD, while on the other hand, the strong oxidizing activity and hyperosmotic state associated with high concentrations of uric acid aggravate the formation of IDD. In addition, when MSU crystals accumulate in the endplate and IVD, they lead to a series of mechanical damages and inflammatory reactions that will further accelerate IDD. Further basic and clinical studies are needed to clarify the mechanism of uric acid in the onset and development of IVD degeneration.

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal 7

relationships that could have appeared to in fluence the work reported in this paper.

Acknowledgments This study received financial support from LiaoNing Revitalization Talents Program (XLYC1807131), the Natural Science Foundation of Liaoning Province (20170540294) and the Teaching Reform Research Project of Dalian Medical University(DYLX19010). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Alison Sherwin, PhD, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac) for editing the English text of a draft of this manuscript.

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