Oral Diseases (2014) doi:10.1111/odi.12273 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd All rights reserved www.wiley.com

REVIEW ARTICLE

Osteoimmunology in orthodontic tooth movement C Jiang1,2, Z Li1,2, H Quan3, L Xiao1,2, J Zhao1,2, C Jiang4, Y Wang1,2, J Liu5, Y Gou1,2, S An1,2, Y Huang1,2, W Yu1,2, Y Zhang1,2, W He1,2, Y Yi1,2, Y Chen1,2, J Wang1,2 1

State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan; 3Qingdao First Sanatorium of Jinan Military Distract of PLA, Qingdao, Shandong; 4Department of Prosthodontics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong; 5Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

The skeletal and immune systems share a multitude of regulatory molecules, including cytokines, receptors, signaling molecules, and signaling transducers, thereby mutually influencing each other. In recent years, several novel insights have been attained that have enhanced our current understanding of the detailed mechanisms of osteoimmunology. In orthodontic tooth movement, immune responses mediated by periodontal tissue under mechanical force induce the generation of inflammatory responses with consequent alveolar bone resorption, and many regulators are involved in this process. In this review, we take a closer look at the cellular/molecular mechanisms and signaling involved in osteoimmunology and at relevant research progress in the context of the field of orthodontic tooth movement. Oral Diseases (2014) doi:10.1111/odi.12273 Keywords: osteoimmunology; orthodontic tooth movement; inflammation; osteoblast; osteoclast; immune factor

Introduction Traditionally, the endocrine system has been acknowledged to be in the mainstream of the regulatory system of bone formation and resorption; however, accumulating evidence has suggested that the skeletal and immune systems share a multitude of regulatory molecules, including cytokines, receptors, signaling molecules, and signaling transducers, thereby mutually influencing each other (Walsh et al, 2006; Takayanagi, 2007). Ontogenically, the development of bone cells has also been revealed to be supported by cells of the immune system; for instance, macrophages encourage osteoblastogenesis by Correspondence: Jun Wang, State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd section, People’s South Road, Chengdu, Sichuan 610041, China. Tel: +86 028 85501425, Fax: +86 028 85501425, E-mail: [email protected] Received 19 May 2014; revised 18 June 2014; accepted 26 June 2014

the secretion of interleukin-18 (IL-18) (Cornish et al, 2003), and T cells are capable of influencing osteoclastogenesis by the secretion of various cytokines such as, IL-1, IL-6, interferon-c (IFN-c), and IL-4 (Takayanagi et al, 2000; Mirosavljevic et al, 2003). On the other hand, cells that regulate bone turnover are derived from the same precursors as inflammatory immune cells and may restrict themselves anatomically, in part by utilizing a signaling network analogous to lymphocyte co-stimulation (Karsenty and Wagner, 2002; Theill et al, 2002). Furthermore, bone homeostasis is often influenced by immune responses, particularly when the immune system has been activated or becomes diseased. For example, in pathological conditions such as arthritis, infiltrating lymphocytes and other mononuclear cells provide several key factors that influence bone metabolism by altering the balance between bone-forming osteoblast (OBs) and boneresorbing osteoclasts (OCs) (Walsh et al, 2006). In 2000, Aaron and Choi first used the term ‘osteoimmunology’ to highlight conditions such as autoimmune and other inflammatory diseases (Arron and Choi, 2000). Recently, the scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions. The framework of osteoimmunology will provide a scientific basis for future therapeutic approaches to diseases related to both of these systems. Orthodontic tooth movement is mediated by the coupling of bone resorption on the compressed side of the periodontal ligament (PDL) and bone formation on the stretched side of the PDL, and immune responses mediated by periodontal tissue under mechanical force might induce T-cell activation and thereby generate an inflammatory reaction with consequent bone resorption (Davidovitch et al, 1988; Verna et al, 1999; Bartzela et al, 2009; Graves et al, 2011). Recently, some researchers have found that many immune factors are involved in the process of orthodontic tooth movement, such as osteotropic hormones, inflammatory mediators, and growth factors (Di Domenico et al, 2012). Orthodontic tooth movement is in fact a good mirror of osteoimmunology, which consists of immune reactions and bone remodeling. Here, we

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will take a closer look at the cellular/molecular mechanisms and signaling involved in osteoimmunology and at relevant research progress in the context of the field of orthodontic tooth movement.

The fundamental knowledge of osteoimmunology Recently, the fundamental knowledge of osteoimmunology has matured such that key cellular and molecular mechanisms governing the homeostasis of the skeletal and immune systems are largely understood. Osteoclasts and osteoblasts are the central players in bone remodeling, and they interact with the immune cells by secreting cytokines or through cell–cell contact. In this section, we will provide a brief description of the current understanding of osteoimmunology from the aspects of osteoclasts and osteoblasts. Osteoclasts Osteoclastogenesis signaling pathways. Characterization of the functions of receptor activator for nuclear factor-jB ligand (RANKL) and its receptors has contributed significantly to the emergence of osteoimmunology, especially with respect to the examination of the interplay between active immunity and the maintenance of bone homeostasis. RANKL, which belongs to the tumor necrosis factor (TNF) superfamily, is a critical cytokine that directs the terminal differentiation of osteoclast precursors, and at the same time, it stimulates and maintains resorptive activity in mature cells (Kong et al, 1999; Suda et al, 1999; Kacena et al, 2005). RANKL is extensively expressed in mesenchymal stem cells such as osteoblast/stromal and synovial cells, and its expression can be upregulated by osteoclastogenic factors, such as vitamin D3, prostaglandin E2 (PGE2), parathyroid hormone, IL-1, IL-6, IL-11, IL-17, and TNF-a (Karsenty and Wagner, 2002; Nakashima et al, 2000). The biologically active receptor for RANKL is RANK, a type I transmembrane protein, which, similar to other members of the TNF receptor family, assembles into a functional trimer (Anderson et al, 1997; Wong et al, 1997). RANK is expressed in osteoclast progenitor cells and mature osteoclasts. Osteoprotegerin (OPG), a potential inhibitor of osteoclastogenesis, was cloned in 1997 (Yasuda et al, 1998a,b) and was subsequently found to associate with a transmembrane protein of the TNF superfamily and function as a decoy receptor (Lacey et al, 1998; Teitelbaum, 2000). RANK signaling in osteoclasts is initiated upon the binding of RANKL to the extracellular domain of RANK, which passes the signaling along to tartrate resistant acid phosphatase 6 (TRAF6). Then, IjB kinase (IKK) and mitogen-activated protein (MAP) kinase are activated, which, in return, modulate the transcriptional activities of the NF-jB and AP-1 families, respectively. Upon activation, IKK phosphorylates the inhibitor of NF-j B, IjB, which results in the translocation of NF-jB to the nucleus and the activation of transcription (Stancovski and Baltimore, 1997). MAP kinases are Ser/Thr kinases that include JNKs/ASPKs, ERKs, and p38s (Chang and Karin, 2001). Direct phosphorylation and transcriptional activaOral Diseases

tion of AP-1 components by MAP kinases lead to the stimulation of AP-1 activity (Karin, 1996). Consequently, nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation, is induced and translocated to the nucleus, promoting the expression of key osteoclast genes (Nakashima and Takayanagi, 2008). Although the binding of RANKL has been demonstrated to be the essential signaling for osteoclast differentiation, co-stimulatory pathways are also required for this process. An immunoreceptor tyrosine-based activation motif (ITAM), which is contained in the co-stimulatory molecules DNAX-activating protein (DAP12) and the Fc receptor common gamma chain (FcRc), is critical for the activation of calcium signaling (Koga et al, 2004). Osteoclast-associated receptor (OSCAR) and trigger receptor expressed on myeloid cells (TREM-2) interact with FcRc and DAP12, respectively. This signaling cascade activates phospholipase Cc(PLCc) and subsequent intracellular Ca2+ release, leading to the nuclear translocation of NFATc1 and the subsequent transcription and autoamplification of NFATc1 (Sato et al, 2006; Ang et al, 2007). The two signaling pathways in osteoclastogenesis are illustrated in detail in Figure 1. Influence of cytokines on osteoclasts. Many cytokines are known to influence osteoclastogenesis and the resorptive ability of osteoclasts; meanwhile, a majority of these cytokines are produced by cells of the immune system (Stashenko et al, 1987a,b). Most of these cytokines act indirectly by regulating the expression of RANK on osteoclasts, or they moderate the intracellular signaling mediated by RANK. It has been reported that TNF-a, IL-6, IL-8, IL-11, IL-17, IL-32, and others directly or indirectly promote osteoclastogenesis; at the same time, IL-10, IL-4, IL-18, IFN-c, and others exert inhibitory effects, whereas TGF-b, IL-7, IL-12, and IL-23 have been found to have both osteoclastogenic and anti-osteoclastogenic properties. Table 1 summarizes the effects of the various cytokines on osteoclasts and the possible underlying mechanisms. Osteoblast Osteoblasts are derived from a mesenchymal progenitor cell that has multipotential properties and can also differentiate into marrow stromal cells and adipocytes (Aubin, 2001). It is widely accepted that osteoclasts have long been the center of attention in osteoimmunological studies due to their hematopoietic origin and strong activation through cytokines. However, the osteoclast’s counterpart, the osteoblast, has recently entered the spotlight, and novel functions of its descendant, the osteocyte, have been elucidated (Rauner et al, 2013). The influence of osteoblasts on hematopoietic stem cells (HSCs). Scholars have described the indispensable role of osteoblasts in the establishment of hematopoietic stem cell niches, as well as in the engraftment and maintenance of HSCs (Jung et al, 2005; Neiva et al, 2005; Dazzi et al, 2006). Located in the bone marrow, HSCs are responsible for the continuous production of blood cells in an adult

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Figure 1 Two signaling pathways in osteoclastogenesis

organism. Their capacity for self-renewal and ability to differentiate into multiple cell types rely heavily on the surrounding microenvironment, which is also defined as the stem cell niche. Taichman and Emerson have noted that osteoblasts play a crucial role in stem cell maintenance due to intimate cell-to-cell contact via integrins (Taichman and Emerson, 1998). In addition, osteoblastic cells have the ability to induce hematopoietic cells to differentiate into bone-resorbing osteoclasts by producing macrophage colony-stimulating factor (M-CSF) and RANKL (Grzibovshis et al, 2010). Bone lining cells, one possible destiny of fully differentiated osteoblasts, have been reported to be responsible for the initiation of bone remodeling by matrix degradation (Everts et al, 1992), whereas osteocytes, the other form of terminally differentiated osteoblasts, act as mechanosensors in bone tissue, thereby regulating bone mass and structure (Burger and Klein-Nulend, 1999; Yeni et al, 2001; Cowin, 2002; Power et al, 2002). Kronenberg used a chimeric mouse model to demonstrate the inhibition of HSC homing into the bone marrow after the deletion of the G-protein Gsa (Kronenberg, 2006). Furthermore, Kronenberg et al have reported the supporting effects of osteogenic PTHs in HSC maintenance by stimulating bone lining cells to produce N-cadherin, which is important for stem cell attachment, and jagged-1, which activates notch receptors on HSCs (Marie, 2002). In one investigation, a quiescent and anti-apoptotic subpopulation of HSCs was identified adhering to osteoblasts via the receptor tyrosine kinase Tie2 on HSCs and angiopoietin1 on osteoblasts. Moreover, the interaction of Tie2 with angiopoietin-1 not only increased the cadherin- and integrin-mediated cell adhesion to osteoblasts but also maintained the long-term repopulating activity of HSCs (Aerssens et al, 1998). Regulating OBs by cytokines. A variety of cytokines are known to regulate osteoblastic cells. Among these, G-CSF,

IL-1, IL-3, IL-6, and IL-17 inhibit the differentiation of osteoblasts, whereas IL-10 and IL-18 decrease overall bone loss. TNF-a is potently pro-apoptotic for osteoblasts, possibly through induction of the Fas-FasL system. IFN-c is reported to inhibit OB proliferation and has variable effects on osteoblast differentiation. Here, a brief summary of cytokines is presented in Table 2.

Osteoimmunology in orthodontic tooth movement RANKL/RANK/OPG system As previously stated, characterization of the functions of RANKL and its receptors (RANK and OPG) has contributed significantly to the emergence of osteoimmunology, especially with respect to the interplay between immunity and maintenance of bone homeostasis (Walsh et al, 2006; Takayanagi, 2007). In vivo studies have shown the presence of RANKL and RANK in periodontal tissues during experimental tooth movement of rat molars and have also shown that PDL cells under mechanical stress may induce osteoclastogenesis through upregulation of RANKL expression (Tyrovola et al, 2008). Considering the importance of RANK, RANKL, and OPG in physiological osteoclast formation, it is reasonable to propose that the RANKL/RANK/OPG system plays an important role in orthodontic tooth movement. It has been found that concentrations of RANKL in gingival crevicular fluid (GCF) increased during orthodontic tooth movement, and the ratio of concentration of RANKL to that of OPG in the GCF was significantly higher than that in control sites. RANKL is expressed in PDL fibroblasts and in osteoblasts on the compressed side of the PDL, and osteoclast differentiation is critically regulated by RANKL, which is produced as a local factor in response to mechanical stress (Yokoya et al, 1997). It has been shown that when the RANKL gene is transferred to periodontal tissue, osteoclastogenesis is activated and the Oral Diseases

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Table 1 Cytokines regulating osteoclastic cells

Cytokines

Overall effects on bone loss

Possible mechanisms

References

TNF-a



Stimulate RANKL-induced osteoclastogenesis; induce RANKL

IL-1 IL-4

↑ ↓

IL-6



IL-7

↑↓

IL-8 IL-10

↑ ↓

IL-11 IL-12

↑ ↑↓

IL-13



IL-15



IL-17



IL-18



IL-23

↑↓

IL-32



IL-33 IFN-a

↓ ↓

IFN-b



IFN-c



Induce RANKL in stromal cells Inhibit RANKL-induced NFATc1 and c-Fos expression; increase OPG and decrease RANKL via a STAT6-dependent pathway; involved in production of a novel T-cell surface-associated molecules Enhance expression of RANKL and OPG, but decrease RANK expression Upregulate production of osteoclastogenic cytokines by T cells, such as RANKL and TNF-a; inhibit osteoclastogenesis in vitro and in vivo Stimulate RANKL expression Induce NO; enhance the expression of OPG and downregulate the expression of RANKL and colony-stimulating factor-1 (CSF-1) Increase the ratio of RANKL/OPG Enhance the production of IL-1b and Th1 cytokines; indirectly reduce RANKL-induced osteoclast differentiation by degradation of TRAF6; inhibit osteoclastogenesis indirectly via T cells Increase OPG and decrease RANKL and RANK in a STAT 6-dependent pathway Stimulate the differentiation of osteoclast precursors into pre-osteoclasts Stimulate osteoclastogenesis by acting on osteoblasts to increase COX-2-dependent PGE2 synthesis and RANKL expression; induce osteoclastogenesis from human monocytes Inhibit TNF-a-induced osteoclastogenesis by the production of NO; inhibit osteoclast formation via T-cell production of GM-CSF Induce osteoclastogenesis via IL-17, RANKL, and TNF-a; inhibit osteoclastogenesis indirectly through activated T cells Activate the NF-jB and MAP kinase pathway, upregulate NFATc1, OSCAR, and cathepsin K; induce expression of TRAcP and VNR Decrease osteoclastogenesis Decrease bone TRAcP type 5b, calcium-phosphate resorption activity and c-Fos expression Inhibit osteoclast differentiation via RANKL-induced c-Fos signaling; increase RANKL-induced NO release as a negative feedback signal during osteoclastogenesis; inhibit osteoclastogenesis via expressing CXCL11 Inhibit RANK signaling; inhibit 1,25 (OH)2D3, parathyroid hormone (PTH) and IL-1-mediated osteoclastogenesis; decrease cathepsin K

rate of orthodontic tooth movement is significantly increased (Kanzaki et al, 2006). Local RANKL gene transfer might be a useful tool not only for shortening orthodontic treatment, but also for moving ankylosed teeth, where the teeth have fused to the surrounding bone. OPG is considered to be a key negative regulator of osteoclastogenesis in the PDL during tooth movement. It seems that on the tensile side of the PDL, there is an increase in OPG synthesis (Sato et al, 2000a,b), and local delivery of OPG inhibits mechanically mediated bone remodeling in orthodontic tooth movement (Lossdorfer et al, 2002). The expression of OPG is modulated by various cytokines, peptides, hormones, and drugs. Cytokines that upregulate OPG expression include TNF-a, IL-1a, IL-18, TGF-b, BMP, and steroid hormones, for example, 17b-estradiol (Sato et al, 2000a,b; Shang et al, 2014), while glucocorticoids and immunosuppressant cyclosporOral Diseases

Hofbauer et al (1999), Quinn et al (2000), Zhang et al (2001) Hofbauer et al (1999), Wei et al (2005) Mirosavljevic et al (2003), Kamel Mohamed et al (2005), Palmqvist et al (2006), Stein et al (2008), Cheng et al (2011) Palmqvist et al (2002) Weitzmann et al (2000), Lee et al (2003), Toraldo et al (2003) Aguila et al (2012) Bendre et al (2003) Sunyer et al (1996), Liu et al (2006) Horwood et al (1998a,b) Queiroz-Junior et al (2010), Nagata et al (2003), Horwood et al (2001) Yamada et al (2007), Stein et al (2008) Ogata et al (1999) Kotake et al (1999), Koenders et al (2005), Yago et al (2009) Horwood et al (1998a,b), Morita et al (2010), Kitaura et al (2011) Kamiya et al (2007), Yago et al (2007), Quinn et al (2008), Duvallet et al (2011) Mabilleau and Sabokbar (2009) Schulze et al (2011), Keller et al (2012) Avnet et al (2007) Takayanagi et al (2002), Coelho et al (2005), Zheng et al (2006) Takahashi et al (1986), Takayanagi et al (2000), Kamolmatyakul et al (2001)

ine A, parathyroid hormone, PGE2, and basic fibroblast growth factor (bFGF) suppress the expression of OPG (Suda et al, 1999). As in osteoclasts, RANKL is also expressed in odontoclasts, suggesting an autocrine or paracrine effect of this regulator on these cells (Lossdorfer et al, 2002). RANKL regulates odontoclast differentiation and dose-dependently increases resorbing activity of odontoclasts. In addition, odontoblasts and fibroblasts, which express RANKL, interact with mononuclear progenitors and produce active odontoclasts. A similar cascade of events leads to physiological root resorption when there is no permanent successor. OPG suppresses the RANKL-induced activation of resorbing activity of odontoclasts (Zhang et al, 2004). Nevertheless, it has been suggested that the RANKL to OPG ratio in periodontal ligament cells contributes to root resorption during orthodontic tooth movement (Nishijima

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Table 2 Cytokines regulating osteoblastic cells

Cytokines

Overall effects on bone loss

TNF-a



IL-1 IL-3

↑ ↑↓

IL-4



IL-7

↑↓

IL-10



IL-13



IL-17 IL-18 IFN-c

↑ ↓ ↑↓

GM-CSF



Possible mechanisms

References

Inhibit OB differentiation, collagen synthesis; induce OB apoptosis through Fas/Fas-ligand signaling Enhance RANKL production Inhibit OB differentiation; promote OB differentiation in MSCs Suppress prostaglandin synthesis; chemoattractant for OBs; stimulate OB proliferation and inhibit OB differentiation Effects depend on whether IL-7 is injected systemically or locally Suppress production of osteoblastic proteins; inhibit the onset of mineralization Suppress prostaglandin synthesis in bone; chemoattractant for OBs Induce RANKL and prostaglandin expression Is a mitogen of osteoblastic cells in vitro Inhibit OB proliferation; variable effects on OB differentiation Inhibit OBs from responding to bone morphogenetic protein (BMP)

et al, 2006). Thus, it can be seen that RANKL and OPG are involved in physiological and pathological root resorption. Parathyroid hormone-related peptide (PTHrP) increases RANKL and downregulates OPG expression by dental follicle cells and human PDL cells via a cAMP/ PKA protein kinase-independent pathway, consequently leading to the physiological root resorption of deciduous teeth and the successful eruption of permanent teeth (Boabaid et al, 2004; Fukushima et al, 2005). M-CSF, which is expressed by odontoblasts, ameloblasts, and dental pulp cells, is also involved in the differentiation and activation of localized pre-odontoclasts. The underlying mechanism of its action seems related to upregulation of RANK and downregulation of OPG gene expression (Wise et al, 2005). Cytokines IL-1b, PGE2, and TNF-a or hormones such as dexamethasone and 1,25(OH)2 D3, induced by the weakened PDL, stimulate the expression of RANKL by PDL fibroblasts and, consequently, the recruitment of active odontoclasts, and the initiation of root resorption. RANKL and OPG in periodontal tissue are important determinants for the regulation of bone remodeling during orthodontic tooth movement as well as root resorption. Determination of serum OPG and s-RANKL can give insight into the regulation of bone homeostasis by the RANKL/RANK/OPG system, and monitoring their concentrations might be useful for predicting the rate of bone remodeling during orthodontic tooth movement from the net effects between bone remodeling and root resorption. Immune factors Bone remodeling that occurs during orthodontic tooth movement is a biological process involving an acute inflammatory response in periodontal tissues. Orthodontic tooth movement is an interaction between the skeletal system and the immune system in which many immune cytokines play important roles. Uematsu S et al have

Centrella et al (1988), Jilka et al (1998), Gilbert et al (2000) Stashenko et al (1987a,b), Jimi et al (1998) Jimi et al (1998), Barhanpurkar et al (2012) Lewis et al (1993), Lind et al (1995), Onoe et al (1996), Ura et al (2000) Weitzmann et al (2000) Van Vlasselaer et al (1993), Owens et al (1996), Hong et al (2000) Lind et al (1995), Owens et al (1996) Kotake et al (1999) Cornish et al (2003) Gowen et al (1988), Smith et al (1987) Kuwabara et al (2001), Oda et al (2005)

found that IL-1b, IL-6, TNF-a, epidermal growth factor (EGF), and beta 2-microglobulin levels are elevated in GCF during human orthodontic tooth movement (Uematsu et al, 1996). Other cytokines were also detected, such as TGF-b1 and PGE2 (Grieve et al, 1994). In this section, we will introduce the cytokines involved in orthodontic tooth movement and their underlying mechanisms. TNF-a is a classical mediator of the inflammatory response that has been shown to be involved in the process of bone resorption. In orthodontic tooth movement experiments, TNF-a plays a prominent role in the mechanism controlling the appearance of osteoclasts at compression sites (Sandy et al, 1993; Brezniak and Wasserstein, 2002). This cytokine is produced primarily by activated monocytes and macrophages, but it is also produced by osteoblasts and has been proven to be an activator of osteoclastic bone resorption (Lowney et al, 1995). Another study found that heavy interrupted force induces a rapid release of TNF-a, and the tissue response continues for a long time period (Karacay et al, 2007). IFN-c is secreted by T-helper 1 (Th1) cells, cytotoxic T cells, dendritic cells, and natural killer cells (Dunn et al, 2006), and it has been characterized as activating macrophages by upregulating nitric oxide (NO) production and major histocompatibility complex (MHC) expression (Biliau et al, 1998). It has been demonstrated that IFN-c was expressed on the compressed side of teeth in a rat tooth movement model and had been evaluated histomorphometrically during orthodontic tooth movement, which increases the trabecular bone volume and decreases the trabecular separation number (Alhashimi et al, 2000; Mermut et al, 2007). Another study showed that IFN-c was induced in experimental tooth movement and could inhibit mechanical force-loaded osteoclastogenesis and tooth movement via its inhibitory action on excessive osteoclastogenesis. Oral Diseases

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IL-1b is one of the most abundant cytokines in the periodontal environment during the initial stages of orthodontic tooth movement because of its direct effects on alveolar bone resorption induced on the compressed side by mechanical loading (Bletsa et al, 2006). IL-1b participates in the survival, fusion, and activation of osteoclasts and plays an important role because the amount of tooth movement correlates with the efficiency of bone remodeling in the alveolar process (Teixeira et al, 2010). Some researchers have found that IL-1b mRNA significantly increased in the gingiva of the compressed side after application of mechanical loading in a rat orthodontic treatment model (Lee et al, 2009; Baba et al, 2011). The particular function of IL-1b as a proinflammatory cytokine has been demonstrated by the administration of an exogenous IL-1 receptor antagonist (IL-1Ra) in mice undergoing orthodontic treatment. The number of osteoclasts in the compressed side of the periodontal tissues decreased after histological characterization, and the rate of tooth movement was reduced (Lee et al, 2009). Moreover, IL-1b is considered to be a powerful inducer of IL-6 production (Uematsu et al, 1996). IL-6 regulates the immune response in inflammation sites and has an autocrine/paracrine activity that stimulates osteoclast formation and bone-resorbing activity. It plays an important role in local regulation of bone remodeling and in the acute inflammation at the beginning of orthodontic tooth movement (Uematsu et al, 1996). Orthodontic forces result in an increase of IL-6 expression in periodontal tissues (Uematsu et al, 1996; Ren et al, 2007; Capelli et al, 2011; Van Gastel et al, 2011). In vitro studies have shown that IL-6 is induced after 12 hours of static compressive force on PDL cells and is enhanced by proinflammatory cytokines such as IL-1b, IL-1a, and TNF-a (Okada et al, 1997). However, IL-6 is produced at the beginning of orthodontic tooth movement, and its expression decreases over time (Uematsu et al, 1996; Ren et al, 2007). IL-17 was also detected in PDL tissue subjected to orthodontic force on day 7, and it increased the release of IL-6 from human periodontal ligament cells in a timedependent manner. Moreover, IL-17 stimulated osteoclastogenesis in human osteoclast precursor cells, and these effects were partially supported by an anti-IL-6 antibody. These results suggest that Th17 cells are involved in orthodontic tooth movement and aggravate the process of orthodontically induced inflammatory root resorption (Hayashi et al, 2012). IL-8 is a potent proinflammatory cytokine that is in an important position for the recruitment and activation of neutrophils during inflammation. It is secreted mainly by monocytes and is prominent in regulating alveolar bone resorption during tooth movement by acting in the early inflammatory response (Baggiolini et al, 1989). The production of IL-8 in the local tension site environment was greater than that in the compressed sites, although the initial force on the first day led to a significant increase in the amount of IL-8 at both sites (Tuncer et al, 2005). Vascular endothelial growth factor (VEGF) is an essential mediator of angiogenesis. During orthodontic tooth movement, compressive forces induce angiogenesis in the

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periodontal ligament together with the mediator, VEGF, which is located in vascular endothelial cells, osteoblasts, osteoclasts in resorptive lacunae, fibroblasts adjacent to hyalinized tissue, local necrotic areas in the compressed zone, and in mononuclear cells in periodontal tissues in animals (Miyagawa et al, 2009). VEGF mRNA was also detected in fibroblasts and osteoblasts in the tension area of mouse periodontal ligament during experimental orthodontic tooth movement (Kaku et al, 2001). In another study, the local administration of rhVEGF significantly increased the number of osteoclasts and the rate of tooth movement (Kaku et al, 2001; Kohno et al, 2003). M-CSF stimulates the survival, proliferation, and differentiation of mononuclear phagocytes and their precursors (Stanley et al, 1983; Hume et al, 1988) and is also a crucial factor for osteoclast differentiation (Felix et al, 1990). It has been found that M-CSF and VEGF were mainly detected in osteoblasts and fibroblasts during experimental tooth movement in mice (Kaku et al, 2008). Then, angiogenesis and bone remodeling by VEGF and M-CSF can be promoted successively. An in vitro study showed that cyclic tensile forces increased the expression of VEGF and M-CSF in osteoblastic cells within 24 h (Motokawa et al, 2005). PGE2 is able to mediate the inflammatory response and to induce bone resorption through the stimulation of osteoclast differentiation (Raisz, 1999; Suda et al, 2004). Studies have identified a role of PGE2 in bone remodeling related to orthodontic tooth movement (Yamasaki et al, 1982, 1984; Lee, 1990; Leiker et al, 1995). Higher levels of PGE2 were found in the GCF of teeth undergoing orthodontic movement (Grieve et al, 1994). Mitsui et al have demonstrated that PGE2 production in osteoblasts increased with both strength and duration of compressive force, and PGE2 production was inhibited by the simultaneous addition of indomethacin. Thus, compressive force may stimulate alveolar bone turnover through the production of PGE2 in osteoblasts (Mitsui et al, 2005). The contribution of TGF-b to the skeletal system is controversial. It has been characterized as an inhibitor of osteoclast precursor recruitment and a mediator of suppressed osteoclast activity (Janssens et al, 2005; Kanaan and Kanaan, 2006). TGF-b has been detected during orthodontic tooth movement, but its location was also controversial. Some studies reported that TGF-b1 was present at higher concentrations in the compression sites vs in the tension sites, suggesting that it plays a role in alveolar bone destruction (Pilkington et al, 2001; Itonaga et al, 2004). However, other studies found increased levels of TGF-b in compression and tension sites vs control sites, but not between tension and compression sites (Garlet et al, 2007). Because of these contradictory results, the function of TGF-b in osteoimmunology will be the focus of future research.

Conclusions Orthodontic tooth movement is a good model of osteoimmunology through which the interplay of the immune system and the skeletal system is well demonstrated. However, the understanding of osteoimmunology in

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orthodontic tooth movement and root resorption is still in the early stages; thus, much work still lies ahead. Acknowledgements This work was supported by grants from the National Natural Science Foundation of China (No. 31070825), from the Ministry of Education Program for New Century Excellent Talents (No. 2082604144053), and from the Sichuan Provincial Foundation of China (No. 2010JY0011, 2010JY0010). The authors declare no potential conflict of interests with respect to the authorship and/ or publication of this article.

Author contributions Jun Wang and Chunmiao Jiang have designed this study, Chunmiao Jiang and Zheng Li drafted this paper as well as Huxian Quan revised it critically. The rest of authors helped search for articles and analysis data.

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Osteoimmunology in orthodontic tooth movement.

The skeletal and immune systems share a multitude of regulatory molecules, including cytokines, receptors, signaling molecules, and signaling transduc...
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