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Review Pain and Bone Damage in Rheumatoid Arthritis

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Review Pain and Bone Damage in Rheumatoid Arthritis Review Pain and bone damage in rheumatoid arthritis: role of leukotriene B4 L.-X. Zheng1, K.-X. Li1, F.-F. Hong2, S.-L. Yang1 1Department of Physiology, College ABSTRACT causes bone and cartilage destruction, of Medicine, Nanchang University; Rheumatoid arthritis is a chronic au- pain, joints stiffness, function loss, and 2 Department of Experimental Teaching toimmune disease characterised by pathological alterations in psychologi- Center, Nanchang University, unbearable joint pain as well as bone cal domains, metabolism and vascular Nanchang, China. and cartilage destruction. Although system (1). The recent pathology of RA Lu-Xi Zheng* RA development is greatly controlled, is mainly defined by joint inflamma- Ke-Xin Li* Fen-Fang Hong the pain and bone damage failed to be tion and bone and cartilage destruction, Shu-Long Yang relieved and managed. Leukotriene B4 companied with the severe pain, result- *These authors contributed equally to (LTB4) has been proved to play an es- ing in severe damage to various facet of this work. sential role in the induction of pain and life and diminish life quality (2, 3). It is Please address correspondence to: bone damage. The nerve injury of RA estimated that approximately 0.5–1% Dr Shu-Long Yang, can promote the production of LTB4, of the population in developed regions Department of Physiology, College which act on their receptors, leading are affected by RA and is more preva- of Medicine, Nanchang University, to the increased release of pro-inflam- lent in women than in men (4). The dis- Nanchang 330006, China. matory cytokines and ROS to reduce ease can affect individuals at any age E-mail: [email protected] neuron viability and pain threshold. groups, but the onset is more frequent Received on November 18, 2018; accepted Moreover, LTB4-BLT1 activation can in 40s or 50s (5). Much work so far has in revised form on February 18, 2019. also increase intracellular calcium focused on the onset and progression of Clin Exp Rheumatol 2019; 37: 872-878. concentration and neuron excitability RA, which are associated with various © Copyright CLINICAL AND as well as NF-κB pathway activation, aetiologies, including genetics, envi- EXPERIMENTAL RHEUMATOLOGY 2019. which further promote the production of ronment, infection and immunity. MMP-9 and CXC3R-1. The mutual pro- Several excellent reviews describing Key words: LTB4, pain, motion between LTB4 and neutrophil pathogenesis of RA have been widely bone damage, rheumatoid arthritis accumulation accelerates the release detected in multifarious aspects, such of TNF-α and IL-β, which enhance as gene, environment, infection, and both peripheral and central nerve sys- immune system. With the development tem sensitisation. LTB4 also involve in of genome-wide approaches and mul- TrpV1 channel activation and modula- tiple technologies, more than 100 loci tion of P2X3 receptor activation. All have been intensively investigated to be above mechanisms contribute to the associated with the risk and progression development of RA pain. IL-23, cPLA2 of RA (6), prominent among these loci and PI3K increase the production of are major histocompatibility complex- CD11b+Gr1high myeloid subtype and human leukocyte antigen (MHC-HLA) calcium concentration, which promote genes which are mainly implicated to the production of LTB4 and further immune function (7). A host of envi- accelerate IL-17 and TNF activation ronmental factors operate on this ge- as well as calcium influx to conduce netic background to contribute to dis- to osteoclastogenesis, resulting in ag- ease development, such as smoking, gregated bone damage. Our review silica exposure, vitamin D deficiency, Funding: this work was supported by is the first to conclude the signalling and obesity (8). Various infectious fac- theNational Natural Science Foundation pathways and associated molecules in tors have been relevant to RA, such as of China (no. 81660151, 81660751, 81260504); the Science Foundation of the LTB4-induced pain and bone damage. Epstein-Barr virus (EBV), Escherichia Science Commission of Jiang Xi Province coli, cytomegalovirus (9). Consider- in China (no. 20161BBG70067) and Jiangxi Introduction able research efforts have been devoted Provincial Natural Science Foundation of Rheumatoid arthritis (RA) is a chronic to proving that both innate and adap- China (no 20171BAB205085). multisystem autoimmune disease char- tive immune deregulation arbitrate RA. Competing interests: none declared. acterised by synovitis, and generally Various immune cells and molecules 872 Clinical and Experimental Rheumatology 2019 Pain and bone damage in RA: role of LTB4 / L.-X. Zheng et al. largely accumulate in the synovium of Recent therapy is better to aim at both vious studies (24, 25). Cortes-Burgos RA patients, such as neutrophils, mac- disease treatment and relieving pain et al. (26) illustrate that the LTB4 con- rophages, dendritic cells, activated T symptoms. It is urgently needed to de- centration in brain in disease groups cells and B cells, and interleukin (IL)- velop better treatment of RA pain. is three times higher than that in con- 18, IL-6. The imbalance of Th17/Treg trol group, and CJ-13610, an inhibitor cells in RA patients is bias towards Role of LTB4 in RA pain of 5-LO, can suppress the synthesis Th17 cells (10), which secret IL-17, Various cells (endothelial cells, leuko- of LTB4 to ameliorate hyperalgesia, resulting in cartilage and bone damage cytes), inflammatory factors (adhesion which implies leukotrienes and 5-LO (11). Macrophages can be stimulated factors, chemoattractants) and many pathway are important mediators for by tumour necrosis factor (TNF)-α or signal transduction pathways unite to pain. Prostaglandins, the metabolites IL-1 to form osteoclast inducing bone induce this abnormal inflammatory of AA via cyclooxygenase (COX)- absorption (12). response to RA (2, 18, 19). Among of pathway, have complementary effects them, leukotriene B4 (LTB4) plays in pain response with leukotrienes, Pain and RA a vital role in the pathogenesis of RA so that co-administration of 5-LO Pain is a predominant problem for RA and administers to joint pain and de- and COX inhibitors, such as zileuton patients, which starts before the mani- struction. It has been proposed that and indomethacin, can result in bet- festations of disease, then causes dam- there is high concentrations of LTB4 in ter anti-hyperalgesia than either alone age to psychosocial distress and fa- the articular fluid in patients with RA (27). For example, Me-UCH9, a dual tigue (13). Pain in RA can be constant (18), suggesting a strong correlation 5-LO/COX-2 inhibitor, can decreases or intermittent and localised or wide- between LTB4 and RA pathogenesis. the content of LTB4 in paw oedema- spread (14). The pathological mecha- As a pro-inflammatory lipid mediator, tous fluid, and inhibits the inflamma- nisms contributing to pain in early RA LTB4 originates from arachidonic acid tory response and pain thus modulating are attributable to chronic inflamma- (AA), then experiences a series of en- the nociceptive responses and inflam- tion whereas in the developed progres- zymatic catalytic reactions involving in mation (25). It has been described by sion, RA are introduced by not only 5-lipoxygenase (5-LO) which produces Ben et al. that Ficus platyphylla (FP) inflammation but also bone damage leukotriene A4 (LTA4), and leukotriene extract has anti-hyperalgesia effect, and other changes, and the pain pro- A4 hydrolase (LTA4H) which directly which may be due to its dual inhibi- gression in RA also proceeds through hydrolyses LTA4 to LTB4. Another pro- tions on the formation of COX-derived sequential processes. Moreover, low tein, 5-lipoxygenase-activating protein PGs and 5-LO-derived LTs (28). mood may administer to pain develop- (FLAP), is an integral membrane pro- ment and inversely pain further wors- tein that is also required for leukotriene LTB4 induced neutrophils ens mood disturbance (15). Synovial synthesis (20). Studies demonstrate accumulation in hyperalgesia inflammation, such as synovitis, is the that, over 45% of the synthetic LTA4 Neutrophils play an important role in main characteristic of RA correlating produced by 5-LO active leukocytes, the development of both inflammatory to pain severity. Noxious stimulation, are released into extracellular and ab- pain and neuropathic pain. LTB4 can like inflammation, can activate the no- sorbed by the cells, and 5-LO inactive activate and accumulate neutrophils, ciceptive receptors by low intensity leukocytes express LTA4H or leukot- and subsequently increase exudate stimulation which normally cannot in- riene C4 (LTC4) synthase, for further from venules, resulting in hyperalgesia duce pain. Peripheral sensitised tissues LTB4 or LTC4 synthesis (20). LTA4H (29) (Table I). Guerrero et al. (30) dem- continuously release algogenic sub- are expressed in endothelial cells, leu- onstrate that neutrophils are involved in stance to stimulate free nerve ending, kocytes and erythrocytes, but 5-LO LTB4-induced pain in the zymosan-in- transmitting impulse to central nerve is only expressed in neutrophils and duced arthritis (ZIA) rat model. Mean- system to induce pain. The constant mononuclear macrophages. The cells while, in human ZIA model, the LTB4- peripheral stimulation results in the without 5-LO can synthesise LTB4 only induced hyperalgesia is relevant to continual release of neurotransmitter after provided with LTA4 by 5-LO ac- neutrophil accumulation. LTB4 can act and cytokines by afferent fibres in spi- tive cells (21). The pathogenesis of RA on the BLT1 receptors on neutrophils nal dorsal horn, inducing the increased mainly involve LTB4, and the synthesis activating and accumulating neutro- excitability, the wider receptive field, of LTB4 mainly depends on 5-LO and phils, leading to the release of TNF-α, and the improved reaction to noxious LTA4H. Then, LTB4 initiates inflam- which binds the receptors on neurons or non-noxious stimulation of dorsal matory signalling cascades by binding to depolarise neurons membranes, pro- horn neuron to afferent signals, thus its two receptors: BLT1 with high affin- ducing action potentials, which are then leading to continual pain.
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