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. Further- ity and BLT2 with low affinity, resulting transformed to central nerve system to more, pain can trigger more severe in the activation and recruitment of leu- induce pain. There are other multiple outcomes than joint damage in RA pa- kocytes to the synovium, which further products of neutrophils such as IL-2, tients. The pain thresholds for RA pa- leads to pain and bone damage (22, 23). IL-6 and ROS, can result in the reduc- tients are reduced over affected joints The positive effects of 5-LO and LTB4 tion of neuron viability (31). Neutro- and associated with synovitis (16, 17). in hyperalgesia has been stated by pre- phils can also transport leukotriene

Clinical and Experimental Rheumatology 2019 873 Pain and bone damage in RA: role of LTB4 / L.-X. Zheng et al.

Table I. The role of leukotrienes in RA pain.

Pathogenesis Leukotrienes Associated receptors Associated effects Pain References

Nerve injury; neutrophil LTB4↑ BLT1 activation ↑ Intracellular Ca2+↑ ↑ (24) accumulation Neuron excitability↑ ↑ (24)

IL-2, IL-6, ROS ↑ Neuron viability↓ ↑ (31)

TNF-α, IL-β↑ Peripheral sensitisation↑ ↑ (31) CNS activation↑

NF-κB activation↑ MMP-9 and ↑ (36) CXC3R-1↑

TrpV1 channel activation ↑ Nerve fibres activation↑ ↑ (45)

Nerve injury CysLT↑ CysLTR↑ Pro-inflammatory cytokines↑ ↑ (32) Modulate P2X3 receptor activation↑ ↑ (50) ROS↑ Pain threshold↓ ↑ (40)

A4 (LTA4) to other cells to synthesise (ERK1/2), p38 MAPK, and c-Jun NH2 the administration of sulforaphane can Cysteinyl leukotrienes (CysLT), which -terminal kinases (JNK1/2) in spinal reduce microglial reactive oxygen spe- can act on their receptors on glial cells glial cells, and MAPK inhibitors can re- cies (ROS) level, thus attenuating ther- aggravating pain development (32). So verse injury-induced hyperalgesia (37- mal hyperalgesia in SNT-injured mice, activated inflammatory cells can release 39). Through p38 MAPK activation, indicating its strong analgesic effect on -infammatory factors with hyperalgesia 5-LO as the first step of LTs pathway neuropathic pain and important thera effect, such as IL-β and TNF-α, acting can be activated by nerve injury in spi- peutic implications (40). on the receptors on neurons to induce nal microglia, resulting in the increase peripheral sensitisation (33) (Table I). of mechanical hypersensitivity (24). LTB4 activated ion channels/receptors Injury in peripheral nerves induces the Numerous pain-producing agents iden- LTB4 activated NF-κB pathway activation of microglia in spinal cord, tified in the RA synovial fluids can in pain and promotes 5-LO expression through modify the functions of ion channels, Leukotrienes can be effective through p38 protein kinase signalling pathway, such as Transient receptor potential- their G-protein-coupled receptors to ac- then 5-LO catalyses AA metabolism to vanil loid 1 (TrpV1), to excite periph- tivate nuclear factor-kappa B (NF-κB) produce LTB4 and CysLT. LTB4 can eral nociceptors (41). Other multi- pathway, enhancing the combination of directly act on the BLT1 in dorsal root farious cytokines, growth factors, and NF-κB and DNA, as well as improv- ganglion (DRG) to increase intracellu- chemokines have been detected at high ing the expression of various inflam- lar calcium concentration and neuron level in RA synovial fluids, such as matory factors (Table I). Serezani et excitability, leading to nociceptive re- IL-1β, IL-6, and TNF-β, nerve growth al. have reported that, the activation of sponse (24) (Table I). And CysLT by factor, vascular endothelial growth fac- the MyD88-dependent NF-κB pathway their receptors activates microglia to re- tor (VEGF) and C-C motif chemokine requires LTB4-BLT1 recognition (34), lease pro-inflammatory factors, leading receptor ligand 2 (CCL2) (42, 43), and and in the cultured monocytes, LTB4 to nociceptive sensitisation (24). After can sensitise peripheral nerves through activates NF-κB through MAPK and nerve injury, spinal cord microglia pro- specific cell-surface receptors. In the ROS -dependent mechanism (35) (Ta- duce ROS, contributing to descending CFA-induced arthritis, increased ex- ble I). After NF-B pathway is activated, pain threshold (Table I), which is suppression of TrpV1 is involved in both neurons upregulate the expressions of ported by the study of Kim et al. (40) peripheral and central mechanism on MMP-9, chemokine CX3C receptor 1, that NADPH oxidase 2 (NOX2)-de- RA pain onset, and increased puriner- and pro-inflammatory cytokines to- di rived microglial ROS can induce neu- gic P2X3 receptor is related with the rectly modulate the neuron activation or ropathic pain after spinal nerve tran- peripheral mechanism (44). Trpv1, one indirectly activate microglia to promote section (SNT), and the SNT-induced of transient receptor potential channels, pain development (36). thermal hyperalgesia is reversed in is a non-selective calcium channel, NOX2-deficient mice, in which TNF-α mainly located in small and medium MAPK activated 5-LO/LTB4 pathway and IL-1β expression in the spinal nociceptive sensory nerve, as well as in neuropathic pain cord is reduced, suggesting these pro- central nerve system. The structure of Nerve injury can trigger activation inflammatory cytokines are involved LTB4 is similar to Capsaicin, which can of mitogen-activated protein kinases in the development of neuropathic pain directly activate TRPV1 receptors, and (MAPK), which consists of extra- and these cytokines expression require this means LTB4 can have a similar ef- cellular signal-regulated kinase 1/2 NOX2-derived ROS generation. And fect (45). In the DRG of rats, LTB4 can

874 Clinical and Experimental Rheumatology 2019 Pain and bone damage in RA: role of LTB4 / L.-X. Zheng et al. increase intracellular calcium concen- ied adverse events are also stated (54), Osteoclastogenesis and synovial inflam- tration at the same level of Capsaicin, which alarms us to explore more candi- matory can be enhanced by the RANKL and BLT1 receptors are expressed on date targets to relieve bone damage. signalling pathway and proinflamma- the Capsaicin-sensitive C-fibres, which LTB4 activates intracellular calcium tory cytokines, such as IL-23 (61-63). means BLT1 receptors may have a sim- and augments human osteoclastogen- IL-23 can participate in the inductions ilar internal-activity with TRPV1 (46). esis via its two receptors to participate of Th17 cells and pro-osteoclastogenic Through TRPV1 channel or BLT1, in bone and cartilage destruction (55). cytokines including IL-17, RANKL and LTB4 can activate nociceptive nerve fi- To understand the mechanisms evolved TNF to promote the inflammatory bone bres to induce pain (Table I). Purinergic in the bone erosion, the origination loss and osteoclast formation (55). It has receptor X2 (P2X) as an ATP-gated ion of osteoclasts is better to be specified been unmasked that IL17 levels in RA channel, is found on both neurons and (Table II) (56). Osteoclastogenesis is a patients were higher than normal with glial cell (47). The metabolites such as multistep process consisting of prolif- more expression of IL17F rs763780, ATP and ADP can increase the synthe- eration, differentiation, cell fusion, and IL17A rs2275913, and IL17A rs3819024 sis of leukotrienes through the P2X re- multi-nucleation (57). The differentia- polymorphisms (58). IL17 and TNF act ceptor on glial cell surface (48). P2X3, tion of multinucleated giant osteoclasts on the G protein coupled receptors (GP- a member of P2X family, selectively from monocytes and macrophages CRs), particularly BLT1 and BLT2 of expresses on nociceptors, and involves are controlled by macrophage colony- leukotrienes. IL-23 can also stimulate in the transmission of pain signals from stimulating factor (M-CSF) and recep- the production of CD11b+Gr1high my- peripheral nerve to spinal cord (49). tor activator of nuclear factor-κB ligand eloid subtype which plays a main role Masamichi et al. have proposed that (RANKL). In abnormal condition, B10 in the production of LTB4 (63, 64), to together with P2X3 and TRPV1 recep- cells aberrantly produce RANKL to con- further enhance the impacts on LTB4 tors, CysLT2 receptor often express on tribute to the development of bone ero- induced osteoclastogenesis. In addi- unmyelinated and non-peptidergic neu- sion in RA (58). As a member of TNF tion, not only can IL-23 play a key part rons. LTC4, a CysLT2 receptor agonist, superfamily, RANKL binds to his re- in the facilitation of LTB4 production enhances the hyperalgesia produced by ceptor RANK in monocyte-macrophag- and osteoclasts differentiation from the agonist of P2X3 receptor rather than by es induced osteoclast precursor cells, macrophages without RANKL partici- itself, suggesting CysLT2 receptors in mature osteoclasts and dendritic cells pation, but also aggravate the inflam- the DRG neurons act as a modulator of to take effects. It has been investigated matory by activating neutrophil (65)

P2X3 receptor to contribute to the pain that by knocking out Rankl or Rank (Table II). behaviours (50) (Table I). gene, a very rare complication in RA, It is purported that macrophages are osteopetrosis results, which suggests equipped with the two BLT receptors Role of LTB4 in bone osteoclastogenesis is impaired, and os- and key LTB4 synthetases, including and cartilage damage of RA teoclasts are reduced. And the knockout 5-LO, LTA4H. These two receptors Except for pain induced in RA, one of of osteoprotegerin (OPG), a competitor also exist in osteoclasts, which means the predominant symptoms for RA pa- with RANKL by binding to RANK sup- LTB4 can determine macrophages and tients are the bone destruction and car- pressing the activity of RANKL, shows osteoclasts cellular fate by activating tilage degradation, which occur at the osteoporosis, which indicates that there nuclear factors and regulating the tran- beginning stage of RA and aggravate are high concentrations of osteoclasts. scription of the osteoclast-related genes as RA develops. Bone erosion starts in Combining these two studies, it is easy (65). It must also be mentioned that the surface of cartilage and inflamed to conclude the vital roles of RANK LTB4 activates phospholipase C (PLC) synovium with huge amounts of osteo- and RANKL in the production of os- and calcium release activated channel clast. Elevated differentiation and acti- teoclasts. After fully differentiated and (CRAC) to allow calcium influx via vation of osteoclasts specialised in the functional osteoclasts are synthesised BLT1 and BLT2 on the macrophages bone absorption of RA result in bone from (c-fms+)/RANK+ monocytes or (65). BLT1 receptor is not only required erosion and bone destruction. Another macrophages precursor cells by recog- in the production of monocytes, neutro- vital cells, fibroblast-like synoviocytes nising M-CSF and RANKL (59), osteo- phils and LTB4 from the myeloid cells (FLS), which are the main component clasts target at the bone surface and se- via IL-23 overexpression, but also ac- of synovial tissue, maintain the stable crete tartrate resistant acid phosphatase celerates the osteoclast differentiation environment inside joint and produce (TRAP), dathepsin K and matrix metal- by calcium and NF-kB signalling in- pro-destructive proteases, as well as loproteinase 9 (MMP 9) to induce the duced by RANKL. Intracellular calci- cytokines to induce pannus, which bone absorption (60). It is reviewed that um concentrations have a strong impact also facilitates destruction of bone and MM9 activity, which was associated on the osteogenesis as well as enhance cartilage (51). So far, the conventional with TNF-α-308A allele, was higher in the LTB4 synthesis because of calcium- drugs disease-modifying anti-rheuma- erosive RA than in non-erosive RA (58). depended cytosolic phospholipase A2 toid drugs (DMARDs) are supplied for Therefore, inhibition of osteoclastogen- (PLA2). The activation of cPLA2 can improved inflammatory synovitis and esis becomes our destination to prevent be also achieved by the direct effect of meliorate joint damage (52, 53), but var- bone damage. IL-23 and PI3K, which facilitates the

Clinical and Experimental Rheumatology 2019 875 Pain and bone damage in RA: role of LTB4 / L.-X. Zheng et al.

Table II. The mechanism of LTB4 induced osteoclastogenesis and bone damage.

Pathogenesis LTB4 production LTB4 effects Osteoclastogenesis Bone damage References

IL-23 →production of CD11b+Gr1high myeloid subtype↑ ↑ IL-17 and TNF ↑: TRAP, Dathepsin ↑ (55, 60, 63-65) activation↑ K and MMP9↑ cPLA2, PI3K and IL-23 → Ca2+↑ ↑ PLC and CARC↑→ ↑: TRAP, Dathepsin ↑ (60, 65) calcium influx↑ K and MMP9↑

IL-β and TNF-α ↑ IL-β and TNF-α ↑: TRAP, Dathepsin ↑ (60, 65) synthesis↑ K and MMP9↑

LTB4 production via IL-23 receptor LTB4 induced bone damage: and deformity remains the most two SH2 expressed in the macrophages (65) therapeutic approaches distressing symptoms for most people (Table II). Andrographolide can prevent the with RA. Inflammation, peripheral and It is noteworthy that, since RANKL is RANKL induced bone loss by upregu- central pain mechanisms and altered a pro-osteogenetic factor, the combina- lating NF-kB and ERK/MAPK signal- gene expressions and joints structure tion effect on osteoclast differentiation ling pathway to achieve bone resolution all can conduce to RA pain. And both between RANKL and LTB4 cannot be (65). It interferes the phosphorylation of LTB4 and CysLTs take effect in the on- ignored. However, LTB4 can also set IkBα induced by binding of RANK and set and development of RA hyperalge- in motion the calcium influx without TRAF6, which normally initiates TAK1 sia and neuropathic pain leukotrienes the evolvement of RANKL-RANK kinase activity, and further activates by inducing nerve injury, neutrophil pathway in macrophages and promote NF-κB pathway (74, 75). The mecha- activation, as well as stimulating as- osteoclast formation in the absent of nism of Amelexanox is evolved in the sociated signalling pathways and ion RANKL as well (65). These various inhibition of RANKL on three spheres: channel/receptors. In the terms of bone pathways in the osteoclastogenesis and suppressing osteoclastogenesis espe- damage, induced joints stiffness and bone loss can become our alternative cially for onset and late progression by deformity are currently resolved in the therapeutic options in the RA treatment inhibiting activated NF-κB and MAPK, orthopaedic surgery. If the progression (66). as well as associated c-Fos and nuclear of joint injury is slowed down based on IL-β and TNF-α promote LTB4 pro- factor of activated T cells c1 (NFATc1) involved mechanisms, patients are un- duction, which in turn increase IL-β expression, and interrupting mature necessary to connive it until compelled and TNF-α concentration (67-70). osteoclast activity in attachment and to accept surgery, and alleviate no mat- These positive interactions between bone resorption, as well as influencing ter physical suffering or mental surgery. productions of LTB4, and IL-β and bone marrow mesenchymal stem cells Further research is urgently required to TNF-α not just participate in neutro- (BMSCs) activity and gene expression define optimal novel therapeutic strate- phil infiltration, but also induce- dam for osteoclasts differentiation, such as gies with greater efficacy and less ad- age on bone and cartilage. IL-β and TRAP, matrix metalloprotein (MMP9), verse reactions, against RA, especially TNF-α have a destructive function on NFATc1 and Cathepsin K bound by its symptoms pain and bone damage. reconstruction of bone and cartilage in NFATc128 (57). C-Fos activates the RA. TNF-α plays a vital role in early transcription factor NFATc1 for os- References RA and long-term inflammation. It sets teoclasts differentiation (76, 77). And 1. McINNES IB, SCHETT G: Pathogenetic insights from the treatment of rheumatoid ar- in motion collagenase production by signs of bone loss in the ovariectomised thritis. Lancet 2017; 389: 2328-37. synoviocytes, especially collagenase II, (OVX) mouse model are also improved. 2. McINNES IB, SCHETT G: The pathogenesis and damages cartilage matrix, further- HU-308, a synthetic cannabinoid, whose of rheumatoid arthritis. N Engl J Med 2011; more stimulating synoviocytes to pro- suppression on osteoclastogenesis, inac- 365: 2205-19. 3. SOUBRIER M, BARBER CHAMOUX N, TATAR duce PGE2, as well as promoting adhe- tivate NF-κB ligand (RANKL) activity Z, COUDERC M, DUBOST JJ, MATHIEU S: sions of neutrophils onto endothelial to bone marrow-derived osteoblasts and Cardiovascular risk in rheumatoid arthritis. cells to contribute to synovial inflam- stromal cells (78), as well as improving Joint Bone Spine 2014; 81: 298-302. 4. SELMI C, GENERALI E, MASSAROTTI M, mation (71, 72). IL-β mainly induces bone resorption are also proved. Deno- BIANCHI G, SCIRÉ CA: New treatments for local inflammation, which enhances sumab can effectively slow down the inflammatory rheumatic disease. Immunol the absorption of articular bone and development of erosion by inhibiting Res 2014; 60: 277-88. cartilage, thus interfering with bone re- RANKL, but the suppression of carti- 5. DHAWAN SS, QUYYUMI AA: Rheumatoid arthritis and cardiovascular disease. Curr Ath- construction. It is well known that the lage destruction is failed, which needs eroscler Rep 2008; 10: 128-33. production of LTB4, IL-β and TNF-α to be cleared by more researches (79). 6. OKADA Y, WU D, TRYNKA G et al.: Genetics of in the inflammation conduces to the ex- rheumatoid arthritis contributes to biology and drug discovery. Nature 2014; 506: 376-81. cessive leukocytes accumulation in the Conclusions 7. JACOB N, JACOB CO: Genetics of rheuma- synovial fluids, leading to joint damage Although recent progress has been toid arthritis: an impressionist perspective. (73) (Table II). made in the disease treatments, pain Rheum Dis Clin North Am 2012; 38: 243-57.

876 Clinical and Experimental Rheumatology 2019 Pain and bone damage in RA: role of LTB4 / L.-X. Zheng et al.

8. TAN EM, SMOLEN JS: Historical observations receptors induced by peripheral nerve injury 40. KIM D, YOU B, JO EK, HAN SK, SIMON MI, contributing insights on etiopathogenesis of in the spinal cord contribute to the generation LEE SJ: NADPH oxidase 2-derived reactive rheumatoid arthritis and role of rheumatoid of neuropathic pain. Glia 2010; 58: 599-610. oxygen species in spinal cord microglia con- factor. J Exp Med 2016; 213: 1937-50. 25. ARAICO A, TERENCIO MC, ALCARAZ MJ, tribute to peripheral nerve injury-induced 9. ALAM J, JANTAN I, BUKHARI SNA: Rheuma- DOMÍNGUEZ JN, LEÓN C, FERRÁNDIZ ML: neuropathic pain. Proc Natl Acad Sci USA toid arthritis: Recent advances on its etiol- Evaluation of the anti-inflammatory and 2010; 107: 14851-6. ogy, role of cytokines and pharmacotherapy. analgesic activity of Me-UCH9, a dual cy- 41. SHUBAYEV VI, K. KATO, RR MYERS: Cy- Biomed Pharmacother 2017; 92: 615-33. clooxygenase-2/5-lipoxygenase inhibitor tokines in Pain, in Translational Pain Re- 10. KOMATSU N, TAKAYANAGI H: Immune-bone Life Sci 2007; 80: 2108-17. search: From Mouse to Man. In: Kruger L, interplay in the structural damage in rheuma- 26. CORTES-BURGOS LA, ZWEIFEL BS, SETTLE Light AR (Eds.) 2010: Boca Raton, FL. toid arthritis. Clin Exp Immunol 2018; 194: SL et al.: CJ-13610, an orally active inhibitor 42. ANTONELLI A, FERRARI SM, GIUGGIOLI 1-8. of 5-lipoxygenase is efficacious in preclini- D, FERRANNINI E, FERRI C, FALLAHI P: 11. SAMARPITA S, DOSS HM, GANESAN R, RA- cal models of pain. Eur J Pharmacol 2009. Chemokine (C-X-C motif) ligand (CXCL)10 SOOL M: Interleukin 17 under hypoxia mi- 617: 59-67. in autoimmune diseases. Autoimmun Rev metic condition augments osteoclast medi- 27. SINGH VP, PATIL CS, KULKARNI SK: Effect 2014; 13: 272-80. ated bone erosion and expression of HIF-1al- of zileuton in radicular pain induced by her- 43. SCURI M, SAMSELL L, PIEDIMONTE G: The pha and MMP-9. Cell Immunol 2018; 332: niated nucleus pulposus in rats. Inflammop- role of neurotrophins in inflammation and al- 39-50. harmacology 2004; 12: 189-95. lergy. Inflamm Allergy Drug Targets 2010; 9: 12. ITONAGA I, FUJIKAWA Y, SABOKAR A, MUR- 28. CHINDO BA, SCHRÖDER H, KOEBERLE A, 173-80. RAY DW, ATHANASOU NA: Rheumatoid WERZ O, BECKER A: Analgesic potential of 44. WALSH DA, McWILLIAMS DF: Mechanisms, arthritis synovial macrophage-osteoclast standardized methanol stem bark extract of impact and management of pain in rheuma- differentiation is osteoprotegerin ligand-de- Ficus platyphylla in mice: Mechanisms of toid arthritis. Nat Rev Rheumatol 2014; 10: pendent. J Pathol 2000; 192: 97-104. action. J Ethnopharmacol 2016; 184: 101-6. 581-92. 13. ODEGARD S, FINSET A, MOWINCKEL P, 29. WEDMORE CV, WILLIAMS TJ: Control of 45. BANG S, YOO S, OH U, HWANG SW: Endog- KVIEN TK, UHLIG T: Pain and psychological vascular permeability by polymorphonuclear enous lipid-derived ligands for sensory TRP health status over a 10-year period in patients leukocytes in inflammation. Nature 1981; ion channels and their pain modulation. Arch with recent onset rheumatoid arthritis. Ann 289: 646-50. Pharm Res 2010; 33: 1509-20. Rheum Dis 2007; 66: 1195-201. 30. GUERRERO AT, VERRI WA JR, CUNHA TM 46. ANDOH T, KURAISHI Y: Expression of BLT1 14. WALSH DA, McWILLIAMS DF: Pain in rheu- et al.: Involvement of LTB4 in zymosan-in- leukotriene B4 receptor on the dorsal root matoid arthritis. Curr Pain Headache Rep duced joint nociception in mice: participation ganglion neurons in mice. Brain Res Mol 2012; 16: 509-17. of neutrophils and PGE2. J Leukoc Biol 2008; Brain Res 2005; 137: 263-6. 15. COVIC T, TYSON G, SPENCER D, HOWE G: 83: 122-30. 47. VILLA G, CERUTI S, ZANARDELLI M et al.: Depression in rheumatoid arthritis patients: 31. SHAW SK, OWOLABI SA, BAGLEY J et al.: Temporomandibular joint inflammation -ac demographic, clinical, and psychological pre- Activated polymorphonuclear cells promote tivates glial and immune cells in both the dictors. J Psychosom Res 2006; 60: 469-76. injury and excitability of dorsal root ganglia trigeminal ganglia and in the spinal trigemi- 16. HODGE MC, NATHAN D, BACH TM: Plantar neurons. Exp Neurol 2008; 210: 286-94. nal nucleus. Mol Pain 2010; 6: 89. pressure pain thresholds and touch sensitiv- 32. FARIAS SE ZARINI S, PRECHT T, MURPHY RC, 48. BALLERINI P, CICCARELLI R, CACIAGLI F ity in rheumatoid arthritis. Foot Ankle Int HEIDENREICH KA: Transcellular biosynthesis et al.: P2X7 receptor activation in rat brain 2009; 30: 1-9. of cysteinyl leukotrienes in rat neuronal and cultured astrocytes increases the biosynthetic 17. LEE YC, CHIBNIK LB, LU B et al.: The re- glial cells. J Neurochem 2007; 103: 1310-8. release of cysteinyl leukotrienes. Int J Immu- lationship between disease activity, sleep, 33. de OLIVEIRA CM, SAKATA RK, ISSY AM, nopathol Pharmacol 2005; 18: 417-30. psychiatric distress and pain sensitivity in GEROLA LR, SALOMÃO R: Cytokines and 49. MALIN SA, MOLLIVER DC: Gi- and Gq-cou- rheumatoid arthritis: a cross-sectional study. pain. Rev Bras Anestesiol 2011; 61: 255-9, pled ADP (P2Y) receptors act in opposition Arthritis Res Ther 2009; 11: R160. 260-5: 137-42. to modulate nociceptive signaling and inflam- 18. IWAMOTO T, OKAMOTO H, TOYAMA Y, MO- 34. SEREZANI CH, LEWIS C, JANCAR S, PETERS- matory pain behavior. Mol Pain 2010; 6: 21. MOHARA S: Molecular aspects of rheuma- GOLDEN M: Leukotriene B4 amplifies NF- 50. OKUBO M, YAMANAKA H, KOBAYASHI K, toid arthritis: chemokines in the joints of kappaB activation in mouse macrophages FUKUOKA T, DAI Y, NOGUCHI K: Expression patients. FEBS J 2008; 275: 4448-55. by reducing SOCS1 inhibition of MyD88 of leukotriene receptors in the rat dorsal root 19. PU Y, CAO D, XIE C et al.: Anti-arthritis effect expression. J Clin Invest 2011; 121: 671-82. ganglion and the effects on pain behaviors. of a novel quinazoline derivative through in- 35. SANCHEZ-GALAN E, GÓMEZ-HERNÁNDEZ Mol Pain 2010; 6: 57. hibiting production of TNF-alpha mediated A, VIDAL C et al.: Leukotriene B4 enhances 51. BARTOK, B, FIRESTEIN GS: Fibroblast-like by TNF-alpha converting enzyme in murine the activity of nuclear factor-kappaB pathway synoviocytes: key effector cells in rheuma- collagen-induced arthritis model. Biochem through BLT1 and BLT2 receptors in athero- toid arthritis. Immunol Rev 2010; 233: 233- Biophys Res Commun 2015; 462: 288-93. sclerosis. Cardiovasc Res 2009; 81: 216-25. 55. 20. PENG A, HUANG X, LIU R, WANG X, ZHUANG 36. PAN YD, GUO QL, WANG E et al.: Intrathecal 52. WASSENBERG S, RAU R: Radiographic heal- J: [Triptolide inhibits the inflammatory -re infusion of pyrrolidine dithiocarbamate for ing with sustained clinical remission in a sponse of monocytes from rheumatoid arthri- the prevention and reversal of neuropathic patient with rheumatoid arthritis receiving tis patients by regulating miR-155]. Xi Bao Yu pain in rats using a sciatic chronic constric- methotrexate monotherapy. Arthritis Rheum Fen Zi Mian Yi Xue Za Zhi 2014; 30: 635-8. tion injury model. Reg Anesth Pain Med 2002; 46: 2804-7. 21. ZHANG W, DAI SM: Mechanisms involved in 2010; 35: 231-7. 53. SMOLEN JS, LANDEWÉ R, BIJLSMA J et al.: the therapeutic effects of Paeonia lactiflora 37. JI RR, SUTER MR: p38 MAPK, microglial EULAR recommendations for the manage- Pallas in rheumatoid arthritis. Int Immunop- signaling, and neuropathic pain. Mol Pain ment of rheumatoid arthritis with synthetic harmacol 2012; 14: 27-31. 2007; 3: 33. and biological disease-modifying antirheu- 22. YOKOMIZO T: Two distinct leukotriene B4 38. JI RR, GEREAU RW 4TH, MALCANGIO M, matic drugs: 2016 update. Ann Rheum Dis receptors, BLT1 and BLT2. J Biochem 2015; STRICHARTZ GR: MAP kinase and pain. 2017; 76: 960-77. 157: 65-71. Brain Res Rev 2009; 60: 135-48 54. RAMIRO S, SEPRIANO A, CHATZIDIONYSIOU 23. MATHIS SP, JALA VR, LEE DM, HARIBABU 39. TRANG T, BEGGS S, WAN X, SALTER MW: K et al.: Safety of synthetic and biological B: Nonredundant roles for leukotriene B4 P2X4-receptor-mediated synthesis and re- DMARDs: a systematic literature review receptors BLT1 and BLT2 in inflammatory lease of brain-derived neurotrophic factor in informing the 2016 update of the EULAR arthritis. J Immunol 2010; 185: 3049-56. microglia is dependent on calcium and p38- recommendations for management of rheu- 24. OKUBO M, YAMANAKA H, KOBAYASHI K, mitogen-activated protein kinase activation. matoid arthritis. Ann Rheum Dis 2017; 76: NOGUCHI K: Leukotriene synthases and the J Neurosci 2009; 29: 3518-28. 1101-36.

Clinical and Experimental Rheumatology 2019 877 Pain and bone damage in RA: role of LTB4 / L.-X. Zheng et al.

55. CAPPUZZO KA, DELAFUENTE JC: Teripara- TINGER B, BLACK D, CUMMINGS SR: Estro- matoid arthritis: pivotal cytokines involved in tide for severe osteoporosis. Ann Pharmaco- gen replacement therapy and fractures in old- bone degradation and inflammation. J Rheu- ther 2004; 38: 294-302. er women. Study of Osteoporotic Fractures matol Suppl 2002; 65: 3-9. 56. GRAVALLESE EM, MANNING C, TSAY A et Research Group. Ann Intern Med 1995; 122: 72. ABRAMSON SB, AMIN A: Blocking the ef- al.: Synovial tissue in rheumatoid arthritis is 9-16. fects of IL-1 in rheumatoid arthritis protects a source of osteoclast differentiation factor. 65. ZHAI ZJ, LI HW, LIU GW et al.: Andro- bone and cartilage. Rheumatology (Oxford) Arthritis Rheum 2000; 43: 250-8. grapholide suppresses RANKL-induced os- 2002; 41: p972-80. 57. ASAGIRI M, TAKAYANAGI H: The molecular teoclastogenesis in vitro and prevents inflam- 73. FRONZA M, MUHR C, da SILVEIRA DS et al.: understanding of osteoclast differentiation. matory bone loss in vivo. Br J Pharmacol Hyaluronidase decreases neutrophils infiltra- Bone 2007; 40: 251-64. 2014; 171: 663-75. tion to the inflammatory site. Inflamm Res 58. CALABRESI E, PETRELLI F, BONIFACIO AF, 66. BOUCHAREYCHAS L, GRÖSSINGER EM, 2016; 65: 533-42. PUXEDDU I, ALUNNO A: One year in review KANG M, QIU H, ADAMOPOULOS IE: Critical 74. TAKAESU G, NINOMIYA-TSUJI J, KISHIDA S, 2018: pathogenesis of rheumatoid arthritis. role of LTB4/BLT1 in IL-23-induced syno- LI X, STARK GR, MATSUMOTO K: Interleu- Clin Exp Rheumatol 2018; 36: 175-84. vial inflammation and osteoclastogenesis via kin-1 (IL-1) receptor-associated kinase leads 59. ARAI F, MIYAMOTO T, OHNEDA O et al.: NF-kappaB. J Immunol 2017; 198: 452-60. to activation of TAK1 by inducing TAB2 Commitment and differentiation of osteo- 67. SAID MM, BOSLAND MC: The anti-inflam- translocation in the IL-1 signaling pathway. clast precursor cells by the sequential ex- matory effect of montelukast, a cysteinyl Mol Cell Biol 2001; 21: 2475-84. pression of c-Fms and receptor activator of leukotriene receptor-1 antagonist, against 75. KEATING SE, MALONEY GM, MORAN EM, nuclear factor kappaB (RANK) receptors. estradiol-induced nonbacterial inflammation BOWIE AG: IRAK-2 participates in multi- J Exp Med 1999; 190: 1741-54. in the rat prostate. Naunyn Schmiedebergs ple toll-like receptor signaling pathways to 60. AOKI K, SAITO H, ITZSTEIN C et al.: A TNF Arch Pharmacol 2017; 390: 197-205. NFkappaB via activation of TRAF6 ubiqui- receptor loop peptide mimic blocks RANK li- 68. WOO CH, YOU HJ, CHO SH et al.: Leukotriene tination. J Biol Chem 2007; 282: 33435-43. gand-induced signaling, bone resorption, and B(4) stimulates Rac-ERK cascade to gener- 76. ZHANG Y, GUAN H, LI J, FANG Z, CHEN W, LI bone loss. J Clin Invest 2006: 116: 1525-34. ate reactive oxygen species that mediates F: Amlexanox suppresses osteoclastogenesis 61. ASAGIRI M, SATO K, USAMI T et al.: Autoam- chemotaxis. J Biol Chem 2002; 277: 8572-8. and prevents ovariectomy-induced bone loss. plification of NFATc1 expression determines 69. CZARZASTA J, ANDRONOWSKA A, JANA B: Sci Rep 2015; 5: 13575. its essential role in bone homeostasis. J Exp Pro- and anti-inflammatory mediators change 77. NEGISHI-KOGA T, TAKAYANAGI H: Ca2+- Med 2005; 202: 1261-9. leukotriene B4 and leukotriene C4 synthesis NFATc1 signaling is an essential axis of os- 62. BAO Z, GUAN S, CHENG C et al.: A novel an- and secretion in an inflamed porcine endo- teoclast differentiation. Immunol Rev 2009; tiinflammatory role for andrographolide in metrium. Domest Anim Endocrinol 2014; 49: 231: 241-56. asthma via inhibition of the nuclear factor- 49-59. 78. OFEK O, KARSAK M, LECLERC N et al.: kappaB pathway. Am J Respir Crit Care Med 70. JANA B, CZARZASTA J: Effect of lipopoly- Peripheral cannabinoid receptor, CB2, regu- 2009 179: 657-65. saccharide and cytokines on synthesis and lates bone mass. Proc Natl Acad Sci USA 63. BOYLE WJ, SIMONET WS, LACE DL: Osteo- secretion of leukotrienes from endometrial 2006; 103: 696-701. clast differentiation and activation. Nature epithelial cells of pigs. Anim Reprod Sci 79. TANAKA S: Emerging anti-osteoclast therapy 2003; 423: 337-42. 2016; 168: 116-25. for rheumatoid arthritis. J Orthop Sci 2018; 64. CAULEY JA, SEELEY DG, ENSRUD K, ET- 71. BINGHAM CO 3RD: The pathogenesis of rheu- 23: 717-21.

878 Clinical and Experimental Rheumatology 2019