Journal of Rheumatic Diseases Vol. 23, No. 3, June, 2016 http://dx.doi.org/10.4078/jrd.2016.23.3.148 Review Article

Pro-inflammatory Modulating Osteoclast Differentiation and Function

Semun Seong1,2, Jung Ha Kim1, Nacksung Kim1,2 Departments of 1Pharmacology and 2Biomedical Sciences, Chonnam National University Medical School, Gwangju, Korea

In general, bone homeostasis is maintained through the balance between bone formation and resorption. Disruption in this bal- ance results in bone-related diseases such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Often, enhanced osteoclas- togenesis is followed by accelerated bone resorption that is induced by pro-inflammatory cytokines in osteoporosis or rheuma- toid arthritis, and leads to bone destruction. In this review study, factors involved in osteoclast differentiation and function are discussed, and how the prevention of such factors is effective in ameliorating bone loss in osteoporosis or rheumatoid arthritis. (J Rheum Dis 2016;23:148-153)

Key Words. Bone and bones, Osteoclasts, Rheumatoid arthritis, Cytokines

INTRODUCTION RA, a chronic autoimmune disease characterized by bone destruction, erosion, and in synovial Bone tissue maintains homeostasis through a process joints, can result in osteopenia and osteoporosis in severe called bone remodeling, in which bone resorption by os- cases [6-8]. Several studies suggest that irregular osteo- teoclasts and bone formation by osteoblasts are con- clast activation is involved in bone destruction of RA. In tinuously repeated [1]. The balance between resorption addition, pro inflammatory cytokines such as tumor ne- and formation provides a stable rate of bone remodeling. crosis factor alpha (TNF-α), (IL)-1, IL-6, Imbalances due to an ectopic increase or decrease in ei- IL-17, and IL-23 secreted by various immune and non-im- ther process results in diseases, including osteoporosis, mune cells including T cells, B cells, , and fi- osteopetrosis, osteopenia, rheumatoid arthritis (RA), broblast-like synoviocytes are reported to be pro-osteo- and other bone related diseases [2,3]. clastogenic by supporting additional RANKL expression Osteoclasts are originated from hematopoietic lineages. directly or indirectly [9-11]. It has been suggested that ac- Initially, hematopoietic stem cells differentiate into mac- cumulations of pro-inflammatory cytokines and osteo- rophages in the presence of -colony stimulat- clastogenic factors in the synovium induce abnormal os- ing factor (M-CSF) and then further differentiate into os- teoclastogenesis in RA [12]. This abnormally enhanced teoclasts in the presence of both M-CSF and receptor acti- osteoclastogenesis apparently results in bone destruction vator of nuclear factor kappa-B ligand (RANKL) [4]. and implies an importance of osteoclast differentiation in Therefore, M-CSF and RANKL are indispensable factors RA. Therefore, osteoclast is a target of pro-inflammatory for osteoclast differentiation. Once an osteoclast is fully cytokines and an effector in initiating bone destruction differentiated, it secretes proteases such as cathepsin K and joint erosion in RA, which suggests that osteoclasto- and matrix metalloproteinase (MMP) to degrade bone genesis should be carefully controlled to maintain normal matrix [5]. bone remodeling or to reduce the progression of ectopic

Received：June 2, 2016, Revised：June 7, 2016, Accepted：June 11, 2016 Corresponding to：Nacksung Kim, Department of Pharmacology, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju 61469, Korea. E-mail：[email protected] pISSN: 2093-940X, eISSN: 2233-4718 Copyright ⓒ 2016 by The Korean College of Rheumatology. All rights reserved. This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

148 Pro-inflammatory Cytokines Regulate Osteoclastogenesis in Bone-related Diseases bone resorption and erosion in RA. In this review, the MAIN SUBJECTS connection between RA and enhanced osteoclasto- genesis will be approached by providing an overview of alpha pro-inflammatory -mediated osteoclastogenesis TNF-α is a cytokine that is produced during inflam- in RA. mation in RA and is able to induce osteoclastogenesis, ei- ther through the upregulation of M-CSF and RANKL ex- pression in osteoblasts and osteocytes [13,14] or in- dependent of RANKL- RANK signaling (Table 1) [15]. In

Table 1. Roles of pro-inflammatory cytokines in osteoclastogenesis Cytokines Effects on osteoclasts Effects on osteoblasts Effects of antibody/blockade Sources TNF-α Enhances osteoclastogenesis Upregulates M-CSF and Inhibitor utilization alleviates Macrophages independent of RANKL in osteoblasts synovial inflammation and RANKL-RANK signaling and osteocytes join erosion pathway Inhibits osteoblastogenesis Prevents systemic bone loss Exhibits pro-osteoclastogenic and nodule formation effects synergistically Induces Dkk-1, Wnt with IL-1 antagonist, to inhibit osteoblastogenesis IL-1 Enhances osteoclastogenesis Stimulates RANKL Decreases cartilage damage Macrophages and prevents osteoclast production and bone resorption by upregulating RANKL expression and stimulating M-CSF production Enhances osteoclastogenesis and bone resorption Mediates TNF-α-induced osteoclastogenesis IL-6 Dual roles on osteoclasts; Induces RANKL Suppresses RANKL- T cells induces bone resorption synthesis in osteoblasts stimulated osteoclast Macrophages Inhibits RANK signaling in differentiation and Synovial fibroblasts osteoclast progenitors in the bone resorption absence of supporting cells IL-17 Supports osteoclastogenesis Upregulates RANKL Reduces bone destruction Th 17 cells dependent of RANKL-RANK expression and joint erosion signaling pathway Enhances the sensitivity of osteoclast precursors to RANKL IL-18 Suppresses osteoclastogenesis Increases OPG Decreases inflammation Macrophages but involved in bone expression in and cartilage degradation Dendritic cells destruction osteoblasts Inhibits TNF-α, IL-6, and Stimulates osteoclastogenesis IFN-gamma secretion by upregulating RANKL production from T cells IL-23 Enhances osteoclastogenesis Direct effect of IL-23 on Suppresses Macrophages Upregulates RANK expression osteoblasts is unknown osteoclastogenesis, Osteoclasts to induce osteoclastogenesis inflammation, and bone destruction IFN: , IL: interleukin, M-CSF: macrophage-colony stimulating factor, OPG: osteoprotegerin, RANKL: receptor activator of nuclear factor kappa-B ligand, Th 17: T helper 17, TNF-α: tumor necrosis factor alpha. www.jrd.or.kr 149 Semun Seong et al. addition, TNF-α is known to inhibit osteoblastogenesis ings suggest an importance of IL-1 blockade as a ther- and nodule formation by downregulating Runx2/Cbfa-1 apeutic treatment. and Osx (Table 1) [16]. Furthermore, TNF-α induces Dkk-1, a Wnt antagonist, to inhibit osteoblastogenesis Interleukin-6 [17]. Meanwhile, TNF-α and IL-1 synergistically induce IL-6, produced by synovial fibroblasts, T cells, and acti- osteoclastogenesis with RANKL [18]. Collectively, these vated macrophages, is responsible for synovial in- pro-osteoclastogenic and anti-osteoblastogenic effects of flammation [29]. Similar to TNF-α and IL-1, IL-6 is also TNF-α result in relatively elevated osteoclastogenesis able to promote RANKL synthesis in osteoblasts [30] and and bone resorption, leading to bone destruction. development of T helper 17 (Th 17), which provides an Such a destructive effect on bone and the inverse corre- extra supplement of RANKL via induction of RANKL ex- lation between bone mineral density and serum TNF-α pression in fibroblast like synoviocytes (Table 1) [31]. levels led to the utilization of TNF-α inhibitors such as Although IL-6 is osteoclastogenic, it has dual roles in infliximab, adalimumab, and golimumab for treatment of osteoclastogenesis. IL-6 induces bone resorption and in- RA [19]. TNF-α inhibitor utilization resulted in alle- hibits RANK signaling in osteoclast progenitors when the viated synovial inflammation and joint erosion (Table 1) additional supporting cells are missing (Table 1) [32]. [20]. Furthermore, it has been reported that TNF-α in- Signal transducer and activator of transcription 3 hibitors prevented systemic bone loss by regulating os- (STAT3) plays a critical role in the stimulation of RANKL teoclastogenesis, whereas little effect was observed on expression. It has been reported that inflammatory cyto- osteoblastogenesis [21]. kines such as TNF-α, IL-1, and IL-6 activate STAT3 in murine osteoblasts either in a direct or indirect manner. Interleukin-1 Furthermore Il-6 is known to stimulate RANKL ex- IL-1 is another pro- produced by pression in osteoblasts through STAT3 activation, and macrophages in inflammatory diseases, which upregu- STAT3 is associated with inflammation and joint destruc- lates RANKL expression and results in enhanced osteo- tion (Table 1) [33]. Therefore, manipulation of STAT3 clastogenesis and bone resorption activity (Table 1) [22]. could be an important therapeutic target in RA. IL-1 also stimulates M-CSF production to suppresses The critical role of IL-6 was verified using IL-6 trans- apoptosis of osteoclasts [23]. Furthermore, IL-1 medi- genic and knockout mice. In IL-6 transgenic mice, it was ates TNF-α-induced osteoclastogenesis; therefore, IL-1 observed that osteoclastogenesis was enhanced, which is able to stimulate osteoclastogenesis independent or de- further resulted in damaged skeletal growth in young pendent of the RANKL signaling pathway [24]. In addi- mice in the prepubertal stage, however, osteoclast for- tion to stimulation of osteoclastogenesis, IL-1 upregu- mation was decreased at the adult stage [34]. In IL-6 lates MMPs and stimulates synovial fibroblasts and chon- knockout mice, decreased osteoclast activity and recruit- drocytes to secrete MMPs and cathepsins [25]. These ment to inflammatory sites were observed [31]. Further- MMPs and cathepsins contribute to cartilage degradation, more, the absence of IL-6 provided protection from ovar- joint destruction, and bone resorption [22]. iectomy-induced bone loss and it has been reported that The importance of IL-1 also has been observed using IL-6 is associated with accelerated bone turnover [35]. IL-1-deficient mice. These mice exhibited reduced osteo- Indeed, IL-6 receptor antagonists have been shown to di- clastogenesis, which led to increased bone density, tra- minish the bone turnover [36] and the IL-6 antagonist to- becular bone mass, and cortical thickness as well as de- cilizumab suppresses RANKL-stimulated osteoclast dif- creased cartilage damage [26]. Therefore, these studies ferentiation and bone resorption (Table 1). Moreover, it suggest that IL-1 blockade might provide a therapeutic alleviated joint destruction in RA patients [37]. There- effect. Although TNF-α inhibitors exhibit beneficial ef- fore, these studies suggest that IL-6 induced bone loss in fects, IL-1 blockade could be also important, because inflammatory diseases could be due to ectopically accel- TNF-α inhibitors are able to reduce inflammation but, erated bone turnover, and usage of IL-6 blockade or anti unable to avoid cartilage damage [27]. However, it has IL-6 is able to improve the accelerated bone turnover by been reported that that antagonism of IL-1β with neu- suppressing osteoclast differentiation and bone resorption. tralizing antibodies exhibited decreased cartilage damage and bone resorption (Table 1) [28]. Therefore, these find-

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Interleukin-17 tion in collagen-induced arthritis [45]. Moreover, soluble IL-17 is a pro-inflammatory cytokine produced by Th 17 IL-17 receptor resulted in reduced joint erosion and in- cells, and its family consists of six members: IL-17A, flammation by downregulating the expression of RANKL IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F [38]. IL-17 and other inflammatory cytokines (Table 1) [9]. receptors are expressed in variety of cells including osteo- According to Genovese et al. [46] utilization of anti-IL-17 blasts, osteoclasts, chondrocytes, and synoviocytes, sug- monoclonal antibody ameliorated RA symptoms in RA gesting that IL-17 is able to influence several cells [39]. patients. Furthermore, a human antibody of IL-17A treat- Stimulation of its ligand results in activation of nuclear ment improved inflammation in synovial joins and clin- factor-κB and mitogen-activated protein , which ical scores in RA patients [47]. Collectively these studies suggests a possibility that IL-17 is involved in osteoclas- suggest that IL-17 blockade may be a putative therapeutic togenesis [40]. Indeed, IL-17 is known to support osteo- for the prevention of joint inflammation and destruction. clastogenesis dependent of the RANKL-RANK signaling pathway. For example, IL-17 enhances the sensitivity of Interleukin-23 and Interleukin-18 osteoclast precursors to RANKL by increasing RANK ex- In addition to the aforementioned major pro-in- pression on the precursors (Table 1) [41]. Furthermore, flammatory cytokines, there are other cytokines involved IL-17 upregulates RANKL expression in several cells in- in osteoclast differentiation such as IL-18 and IL-23. cluding osteoblasts, synovial cells, and mesenchymal IL-23 stimulates IL-17 synthesis to form an axis in order cells, thereby increasing the RANKL/osteoprotegerin ra- to control inflammation [48]. Furthermore, systemic tio and enhancing osteoclastogenesis, ultimately result- IL-23 exposure has been shown to cause chronic arthritis ing in bone destruction (Table 1) [42]. In addition to the and bone loss, which in turn resulted in enhanced osteo- induction of RANKL expression, IL-17 induces the ex- clast differentiation; whereas, IL-23 knockout mice ex- pression and secretion of pro-inflammatory cytokines in- hibited reduced osteoclast maturation [49]. In addition, cluding IL-1, TNF-α, and IL-6 [43]. Such pro-in- it has been reported that IL-23 upregulates RANK ex- flammatory cytokines further enhance synovial in- pression to induce osteoclast differentiation (Table 1) flammation by activating macrophages, lymphocytes, and [50]. On the contrary, anti-IL-23 antibody treatment sup- neutrophils [44]. For example, it has been reported that pressed osteoclast differentiation, inflammation, bone recombinant IL-17 activity is synergistically increased destruction, and ultimately ameliorated collagen-in- with other pro-inflammatory cytokines and ultimately re- duced arthritis (Table 1) [51]. Although IL-18 has been sults in joint inflammation and damage [43]. Such in- reported to suppress osteoclastogenesis, several studies volvement of IL-17 in bone resorption, and cartilage and have indicated that IL-18 is involved in bone destruction joint erosion led to the utilization of anti-IL-17 in RA. [52], wherein, IL-18 stimulates osteoclast differentiation Antibody neutralization exhibited reduced bone destruc- by upregulating RANKL production from T cells in RA

Figure 1. Roles of pro-inflam- matory cytokines in osteoclas- togenesis. Pro-inflammatory cy- tokines are produced from vari- ous immune cells including T cells, B cells, macrophages, den- dritic cells, FLS, etc. Pro-in- flammatory cytokines induce osteoclastogenesis either de- pendent or independent of the RANKL-RANK signaling path- way. FLS: fibroblast-like syno- viocytes, IL: interleukin, RANKL: receptor activator of nuclear factor kappa-B ligand, TNF-α: tumor necrosis factor alpha.

www.jrd.or.kr 151 Semun Seong et al. synovitis (Table 1). IL-18 is able to induce expression of and differentiation: an overview. J Med Dent Sci 2012; both soluble and membrane bound RANKL [53]. It has 59:65-74. 5. Chen YC, Sosnoski DM, Mastro AM. Breast meta- been observed that its effect on osteoclastic formation stasis to the bone: mechanisms of bone loss. Breast Cancer was similar to IL-1β but not as effective as TNF-α. Res 2010;12:215. Although there are contradictory roles for the cytokines, 6. Choy EH, Panayi GS. Cytokine pathways and joint in- flammation in rheumatoid arthritis. N Engl J Med they still have the potential to induce osteoclast differ- 2001;344:907-16. entiation in RA and cause bone destruction. 7. Jung SM, Kim KW, Yang CW, Park SH, Ju JH. Cytokine- mediated bone destruction in rheumatoid arthritis. J Immunol Res 2014;2014:263625. CONCLUSION 8. Schett G, Gravallese E. Bone erosion in rheumatoid arthri- tis: mechanisms, diagnosis and treatment. 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