Srinivasan, J Clin Cell Immunol 2013, S13 http://dx.doi.org/10.4172/2155-9899.S13-007 Clinical & Cellular Immunology Research Article Review Article Open OpenAccess Access The Role of Inflammatory Cytokines and the RANKL-RANK-OPG Molecular Triad in Periodontal Bone Loss-A Review Prathiba Chichurakanahalli Srinivasan* SV Dental Collge, Bangalore, Karnataka, India Abstract Periodontal diseases are chronic inlammatory disorders involving the supporting structures of the teeth. Connective tissue destruction and loss of bone support of the dentition are key features of this disease. Early studies have revealed that bioilm plaque accumulation in the dentogingival area is the primary etiological factor of periodontal diseases. Recent research has not only reinforced the bacterial etiology of periodontal disease, but has also emphasized the role of inlammation in this pathologic process. The host mounts an immune-inlammatory response to combat the bacterial attack. The host response is like a double-edged sword. It eliminates the offending pathogens, but overstimulation and ampliication of the same leads to tissue destruction and bone loss. In the mid1990s, extensive research in the ield of bone biology led to the discovery of the RANKL-RANK-OPG molecular triad. This article explores the mechanisms by which inlammatory host response leads to alveolar bone loss-the role of cytokines, factors that stimulate osteoclastogenesis via the RANKL-RANK-OPG pathway and how inlammation interferes with the uncoupling of bone formation and bone resorption. In addition to the conventional therapeutic modalities aimed at eliminating the microbes, additional therapeutic strategies that interfere with the RANKL-RANKOPG axis may have a protective effect on the bone loss. Keywords: Inlammation; RANKL; OPG; RANK; Osteoclastogenesis; Cytokines; Periodontal disease; IL-1; TNF; Alveolar bone loss Introduction Periodontal diseases, which are chronic inlammatory disorders localized to the attachment structures of the teeth, are considered to be the major cause of tooth loss in adults and the most prevalent form of bone pathology in humans [1]. he term periodontal disease refers to both gingivitis and periodontitis. Gingivitis is an inlammatory condition of the sot tissues surrounding the teeth [2]. If unchecked, gingivitis progresses to periodontitis, an inlammation of the supporting structures of the teeth [3]. Speciic gram-negative anaerobic bacteria species such as Porphyromonas gingivialis and Tannerella forsythia have been associated with periodontitis [4]. he initial host response to bacterial infection is a local inlammatory reaction that activates the innate immune system [5]. An imbalance between the plaque bioilm and the host immune system results in the overexpression of an array of proinlammatory cytokines, propagation of inlammation through the gingival tissues and the subsequent destruction of alveolar bone [6]. hus the inlammatory process results in destruction of connective tissue and alveolar bone, the hallmarks of periodontal disease. he Role of Inlammation in Alveolar Bone Loss here are two critical factors, which dictate whether bone loss occurs in response to inlammatory reaction. 1. he concentration of pro-inlammatory cytokines and mediators present in the gingival tissue must be suicient to activate the pathways leading to bone resorption. 2. he inlammatory mediators must penetrate the gingival tissue to reach within a critical distance to alveolar bone [5]. Page and Schroeder showed that bone resorption ceases when a 2.5 mm zone is created between the site of bacteria and bone [7]. J Clin Cell Immunol Inlammatory Mediators here are several classes of molecules that activate a host response which in turn stimulates osteoclastogenesis either directly or indirectly [8]. hese include lipid-based molecules such as prostaglandins, leukotrienes [8], pro-inlammatory cytokines such as IL-1, IL-6, IL-11 and IL-17, tumor necrosis factor-alpha, leukemia inhibitory factor, and oncostatin M. he kinins such as bradykinin, kallidin and thrombin and various chemokines can also lead to bone resorption [9]. Chemokines are chemotactic cytokines that stimulate recruitment of inlammatory cells. Based on the structure of their ligand, they are divided into two major families-CC and CXC. heir receptors are referred to as CC chemokine receptor (CCR) and CXC chemokine receptor (CXCR). CXCR2 receptor binds several chemokines that are neutrophil chemoattractants [10]. Neutrophil recruitment is important to protect against bacterial attack. Yu JJ et al. conducted a study in which oral gavage of Porphyromonas gingivalis was administered to CXCR2-and IL-17-deicient mice. he results revealed increased periodontal bone loss in these mice compared to wild-type mice, suggesting that chemokines and IL-17 are important in protecting host against pathogen-initiated bone loss. IL-17 is a key cytokine produced by a newly identiied subset of T helper cells (h) called the “h17” lymphocytes and it is important in stimulating chemokine production to recruit neutrophils. he enhanced bone loss observed in this study is the result of a defective ability to stimulate neutrophil migration to the inlamed bone, which requires IL-17 receptor dependant signals, *Corresponding author: Prathiba Chichurakanahalli Srinivasan, SV Dental Collge, Bangalore, Karnataka, India, E-mail: csprati@yahoo.com Received June 13, 2013; Accepted August 27, 2013; Published August 31, 2013 Citation: Srinivasan PC (2013) The Role of Inlammatory Cytokines and the RANKL-RANK-OPG Molecular Triad in Periodontal Bone Loss-A Review. J Clin Cell Immunol S13: 007. doi:10.4172/2155-9899.S13-007 Copyright: © 2013 Srinivasan PC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Innate Response to Infectious Diseases ISSN:2155-9899 JCCI, an open access journal Citation: Srinivasan PC (2013) The Role of Inlammatory Cytokines and the RANKL-RANK-OPG Molecular Triad in Periodontal Bone Loss-A Review. J Clin Cell Immunol S13: 007. doi:10.4172/2155-9899.S13-007 Page 2 of 8 thus underscoring the importance of IL-17 in the defense against oral pathogens [11]. From their study Zhang et al. concluded that IL17A produced by h17 cells stimulate the development of osteoclasts (osteoclastogenesis) in the presence of osteoblasts [12] and Cardoso et al. observed expression of IL-17 in gingiva from patients with periodontitis [13]. he role of pro-inlammatory cytokines, interleukin-1 (IL1) and tumor necrosis factor (TNF) in bacteria-induced bone loss was demonstrated in an animal model study by Assuma et al. Porphyromonas gingivalis (Pg)-soaked silk ligatures were applied to the posterior mandibular teeth of Macaca fascicularis primates to induce experimental periodontitis. he primates received local injections, over a period of 6 weeks, of antagonists to TNF-alpha and IL-1 (soluble TNF-alpha and IL-1 receptors) or vehicle control. he gingival connective tissue sections in close proximity to bone demonstrated signiicant inlammatory cell recruitment and osteoclast formation surrounding bone in the control primates. hus, infection with Pg in these animals was associated with expansion of the inlammatory front to alveolar bone. he antagonists to cytokines reduced the appearance of inlammatory cells in this region and the formation of bone resorbing osteoclasts. hus, inhibition of inlammatory mediators can prevent the “inlammatory front” from reaching the alveolar bone leading to a reduction in bone loss as observed in this animal model [14]. In a follow-up study with the same model Delima et al. in 2001, stated that IL-1 and TNF blockers inhibited the loss of connective tissue attachment [15]. In their study, Graves DT et al. concluded that P. gingivalis induced osteoclastogenesis was reduced in TNF receptor-deicient mice compared to wild-type controls, thus indicating that osteoclast formation resulted from stimulation of the host response rather that from the direct efect of bacterial products [16]. Gaspersic et al in rat ligature model study concluded that the administration of recombinant human TNF-alpha (rhTNF-alpha) accelerated the progression of periodontitis [17]. In a study by Garlet et al. TNF-alpha receptor-1knockout mice developed signiicantly less inlammation and alveolar bone loss in response to Aggregibacter actinomycetemcomitans oral gavage. he levels of the pathogen as quantiied by real-time PCR was higher in the TNF receptor ablated mice, compared to the wild-type controls. he quantitative mRNA expression of inlammatory cytokines IL-1 beta, interferon-gamma, and receptor activator of nuclear factor-kappa B ligand (RANKL) was signiicantly lower in the TNF receptor ablated mice. hus, the absence of TNFR-1 resulted in lower production of cytokines in response to the pathogen. Decrease in TNFalpha seemed to reduce the host response, thereby leading to higher levels of bacteria. However, there was reduced expression of cytokines that stimulate bone resorption, which resulted in less net bone loss [18]. In response to P. gingivalis oral gavage, mice with genetically deleted IL-6 had decreased bone loss compared to wild-type mice, thus indicating the pro-inlammatory efects of IL-6 leading to bone resorption. (Baker PJ et al.) [19]. Li et al. examined the role of B and CD4 T cells in adaptive immunity of rats infected with Aggregatibacter actinomycetemcomitans (Aa). Sprague-Dawley male rats were fed Aa-containing mash or control-mash for 2 weeks. B and CD4 T cells were obtained from draining lymph nodes at 2, 4 and 12 weeks, post inoculation. Quantitative polymerase chain reaction-based messenger RNA expression was conducted for 89 cytokine family genes. B and CD4 T cells of Aa-infected rats increased and were activated, resulting in enhanced isotype-switched serum immunoglobulin G by 2 weeks post inoculation. Bone resorption was evident 12 weeks ater Aa-feeding. In B cells, interleukin-2 (IL-2), macrophage-inhibiting factor, IL-19, ILJ Clin Cell Immunol 21, tumor necrosis factor (TNF), CD40 ligand (CD40L), CD70, bone morphogenetic protein 2 (BMP2), BMP3, and BMP10 were upregulated early; while IL-7, Fas ligand (FasL), small inducible cytokine subfamily E1, and growth diferentiation factor 11 (GDF11; BMP11) were upregulated late (12 weeks). BMP10 was sustained throughout. In CD4 T cells, IL-10, IL-16, TNF, lymphotoxin-beta (LTβ), APRIL, CD40L, FasL, RANKL and osteoprotegerin were upregulated early, whereas IL1β, IL-1RN, IL-1F8, IL-24, interferon-α1, GDF11 (BMP11), and GDF15 were upregulated late (12 weeks). here was upregulation in mRNA for a number of cytokines not normally ascribed to periodontal disease. IL-16 was upregulated in CD4 T cells in the early phase of the response [20]. IL-16 has been shown to be involved in the selective migration of CD4 T cells, and participates in inlammatory diseases [21]. IL-19, a novel cytokine of the IL-10 family, was also upregulated in CD4 T cells in response to Aa [20]. IL-19 produced by synovial cell in Rheumatoid arthritis (RA) patients promotes joint inlammation (Sakurai et al.) [22]. IL-21, which has recently been shown to induce receptor activator of nuclear factor kappaB ligand (RANKL) and was implicated in arthritis (Jang et al.) [23] was upregulated in B cells responding to Aa [20]. By 12 weeks, there was also an induction of IL-24 in CD4 T cells responding to Aa [20]. IL-24 was increased in the synovium of patients with rheumatoid arthritis, and this cytokine was implicated in recruitment of neutrophil granulocytes (Kragstrup et al.) [24]. B cellactivating-factor (BAFF, or TNFSF13B) and a proliferation-inducing ligand (APRIL), members of the TNF family, were upregulated in B cells and CD4 T cells, respectively, in response to Aa infection [20]. IL-23, a proinlammatory cytokine composed of IL-23p19 and IL-12/23p40 subunits, is known to promote the diferentiation of h17 cells. Studies showed that IL-23 and IL-12 were expressed at signiicantly higher levels in periodontal lesions than in control sites, suggesting that IL23-induced h17 pathway is stimulated in inlammatory periodontal lesions (Ohyama et al.) [25]. IL-33 is a new member of the IL-1 family, which plays a role in inlammatory response. Injecting IL-33 or IL-33R agonistic antibody into TNF transgenic mice overexpressing human TNF inhibited the development of spontaneous joint inlammation and cartilage destruction. In vitro, IL-33 directly inhibits mouse and human M-CSF/receptor activator for NF-kβ ligand-driven osteoclast diferentiation, suggesting an important role for IL-33 as a boneprotecting cytokine with potential for treating bone resorption (Zaiss et al.) [26]. he bone resorption protein RANKL and its soluble decoy receptor OPG was also induced in the CD4 T cells of Aa-fed rats [20]. he role of bone morphogenetic proteins (BMPs) and growth diferentiation factors (GDFs) in periodontal disease Bone morphogenic proteins (BMPs) and growth diferentiation factors (GDFs) are members of the transforming growth factor-β (TGF-β) superfamily. hey play important roles during development and organogenesis in delivering positional information in both vertebrates and invertebrates, and are involved in the development of hard as well as sot tissue (Herpin, Lelong and Favrel) [27]. BMP2 was induced in B cells early (week 4) of the inlammatory process, at the same time that RANKL was induced in CD4 T cells (Li et al.). his suggests that bone repair mechanisms were induced early, well ahead of impending bone resorption. However, by 12 weeks of infection by Aa, BMP2 was shut down, as bone resorption proceeded. BMP3 was also upregulated at week 4 in B cells responding to Aa [20]. BMP3 has been shown to be a negative regulator in the skeleton, as mice lacking BMP3 have increased bone mass. Transgenic mice over-expressing BMP3 had altered endochondral bone formation resulting in spontaneous rib fractures [28]. Both BMP2 and BMP3 were upregulated in B cells at the Innate Response to Infectious Diseases ISSN:2155-9899 JCCI, an open access journal Citation: Srinivasan PC (2013) The Role of Inlammatory Cytokines and the RANKL-RANK-OPG Molecular Triad in Periodontal Bone Loss-A Review. J Clin Cell Immunol S13: 007. doi:10.4172/2155-9899.S13-007 Page 3 of 8 same time (4 weeks post infection), and were shut down at 12 weeks, at which time bone resorption was evident [20]. B cells responding to Aa upregulated BMP10 at all time points [20]. BMP10 has been shown to regulate myocardial hypertrophic growth (Chen et al. 2006) [29]. BMP10 may function as a tumor suppressor and apoptosis regulator for prostate cancer [30]. hus the expression of BMP 10 in the Aa rat model at all points suggests it’s role in inlammation and bone resorption [20]. Also the involvement of BMP10 in cardiac hypertrophy [29] and in prostate cancer [30] suggests a possible link between periodontal disease and systemic diseases. Discovery of OPG/RANKL/RANK Molecular Triad he Solving of the Puzzle Growth diferentiation factor 11 (GDF11) or BMP11, plays an important role in establishing embryonic axial skeletal patterns [31]. In the GDF11 was upregulated at 12 weeks post infection, in both B and CD4 T cells, at the time of bone resorption. his suggests that GDF11 may have a novel role in bone resorption [20]. In 1981, Rodan and Martin proposed a novel hypothesis wherein the osteoblast played a central role in mediating the hormonal control of osteoclastogenesis and bone resorption [37]. But, the factors expressed by the osteoblast/stromal cells remained undetermined until they were discovered independently by four groups using diferent approaches. Boyle and coworkers at the Amgen Inc (housand Oaks, CA, USA) discovered OPG serendipitously when they were attempting to identify tumor necrosis factor receptor-related molecules with possible therapeutic utility by generating transgenic mice that overexpress various TNF receptor related cDNAs. Mice over-expressing one particular cDNA developed marked osteopetrosis because they did not have osteoclasts in their bones. he protein encoded by the gene was termed osteoprotegerin-OPG (the bone protector) [38]. he Aa-induced rat model, the Pg-induced mouse model and several other animal studies discussed above strongly support the role of pro-inlammatory cytokines in bone loss. he role of novel cytokines not previously ascribed to periodontal disease has been extensively discussed and these studies also suggest a possible link between periodontal disease and systemic diseases. Using the standard approach to test the Rodan-Martin hypothesis of purifying a factor from human embryonic ibroblasts that inhibited osteoclastogenesis, researchers at Snow Brand Milk Products Co. (Sapporo, Hokkaido, Japan) reported their discovery of an identical molecule. hey obtained a partial protein sequence and subsequently cloned the cDNA for OPG [39]. Osteoimmunology he discovery of OPG became the key to identify the long-sought osteoclast diferentiation factor expressed on osteoblastic/stromal cell that was essential for osteoclast development. Using expression cloning and OPG as a probe, both the groups quickly identiied its ligand, which they termed OPG ligand [40] and osteoclast diferentiation factor [41] respectively. his ligand turned out to be identical to a member of the TNF ligand family, which had been identiied in the preceding year as RANKL [42] and TNF-related activation induced cytokine (TRANCE) [43]. he cellular receptor was identiied as being identical to previously identiied RANK, which Anderson and coworkers at Immunex (Seattle, WA, USA) had discovered while they were sequencing cDNAs from a human bone marrow derived myeloid dendritic cell cDNA library. [42]. Both the groups found that RANK had partial homology to a portion of the extracellular domain of human CD40, a member of the TNF receptor superfamily, and it was involved in the activation of T cells in the immune system. he groups then isolated RANKL by direct expression screening and found, like Wong and coworkers [43] did, that it increased dendritic cell stimulated naïve T cell proliferation and survival of RANK-expressing T cells. hese discoveries led to the conclusion that RANKL is involved in osteoclastogenesis and T cell activation. Extensive research in the ields of immunology and osteology has revealed an intimate relationship between inlammation/the immune system and the skeletal system [32].he immunoskeletal interface involves centralization of the immune and skeletal functions around common cells types and cytokine efectors that control the physiological bone mass. Prolonged immune activation can lead to skeletal deterioration. his interconnection of the skeletal and the immune systems has spawned the emergence of a new ield of science termed “osteoimmunology” [33]. he ield of osteoimmunology ofers better insights into the understanding of pathogenesis of periodontal disease by explaining the role of inlammation in alveolar bone loss. Osteoclasts and the Receptor Activator of NF-Kappa B (RANK)/RANK Ligand (RANKL)/Osteoprotegerin (OPG) System Osteoclasts are unique cells of the human body tasked with resorbing bone. hese multinucleated giant cells bind down onto the bone surfaces creating a sealing zone and a ruled-membrane border into which apical proton pumps accumulate hydrogen ions that combine with chloride ions to form hydrochloric acid, which degrades bone mineral. he exposed collagen matrix is attacked by acid resistant endosomal and lysosomal enzymes that cleave collagen ibers efectively removing small quantities of bone [34]. How osteoclasts form, what regulates their diferentiation and activity was an enigma. Research has revealed that osteoclast precursors circulate amid the monocyte/macrophage population and diferentiate into preosteoclasts that fuse and form giant bone resorbing mature osteoclasts [35]. Inlammatory processes such as rheumatoid arthritis and periodontal infection predispose to osteoclastic bone resorption by production of pro-inlammatory cytokines such as IL-1 and TNFalpha [36]. he osteoclast however, does not possess receptors for the cytokines or hormones. So, for years the biologists were perplexed as to how they resorbed bone. his conundrum was solved with the discovery of the osteoprotegerin (OPG), receptor activator of nuclear factor-kappa B ligand (RANKL) and receptor activator of nuclear factor kappa-B (RANK). J Clin Cell Immunol Osteoclast Formation/Osteoclastogenesis Osteoclastogenesis is coordintated by the interaction of the three members of the TNF superfamily-OPG/RANKL/RANK [44] RANKL is expressed predominantly as a membrane-bound ligand on osteoblasts, ibroblasts, and activated T and B cells and its osteoclastogenic action can be blocked by its soluble decoy receptor osteoprotegerin (OPG) [9,35]. Together with Macrophage-colony stimulating factor (mCSF), RANKL is a key cytokine in the induction of osteoclastogeneis both in vitro and in vivo [45]. It binds directly to RANK on the surface of preosteoclasts and osteoclasts, stimulating both the diferentiation of osteoclast progenitors and the activity of mature osteoclasts [40,46,47]. Regulation of Bone Remodeling - he Role of the RANKL-RANK-OPG System Systemic factors and local stimuli in the bone microenvironment Innate Response to Infectious Diseases ISSN:2155-9899 JCCI, an open access journal Citation: Srinivasan PC (2013) The Role of Inlammatory Cytokines and the RANKL-RANK-OPG Molecular Triad in Periodontal Bone Loss-A Review. J Clin Cell Immunol S13: 007. doi:10.4172/2155-9899.S13-007 Page 4 of 8 target the molecular interplay of RANKL-RANK-OPG cytokine system, thus regulating the remodeling of alveolar bone. (Lerner 2; Boyle et al. Mundy et al. Horowitz et al.) [48-51]. Systemic modulators include calcitonin, parathyroid hormone, thyroid hormone, gonadal steroids, vitamin D, glucocorticoids and growth hormone. Local mediators include pro-inlammatory cytokines as well as prostanoids (Lerner) [48]. Bacterial products may interfere with bone remodeling balance by regulating RANKL expression (Lerner, Henderson and Nair) [48,52]. Gram-negative bacteria such as A. actinomycetemcomitans, (Teng et al. Kikuchi et al. Teng et al. ) [53-55], P. gingivalis (Okahashi et al.) [56], Treponema denticola (Choi et al.) [57] and Streptococcus pyogenes (Okahashi et al. Sakurai et al.) [58,59] have been shown to upregulate RANKL expression in a variety of cells. RANKL-RANK-OPG in Periodontal Disease Studies have revealed that during inlammatory response, cytokines, chemokines and other mediators stimulate periosteal osteoblasts, altering the expression levels of receptor activator of nuclear factorkappa B ligand (RANKL) on the osteoblast surface [9,49]. RANKL is expressed by osteoblasts in the form of a membrane-bound protein (mRANKL) or cleaved into a soluble form (sRANKL) [60,61]. IL-1 stimulates osteoclastogenesis and bone resorption, largely through up-regulation of RANKL, while TNF can stimulate osteoclastogenesis directly or indirectly through RANKL [62]. Inhibition of RANK ligand caused a decrease in alveolar bone loss in several models of periodontal disease (Teng et al. Han et al. Jin et al.) [55,63,64]. Teng et al. in their study demonstrated the role of CD4+ T cells in mediating periodontal bone loss. Also, they found that administration of RANK ligand inhibitor; osteoprotegerin reduced osteoclastogenesis and inhibited alveolar bone destruction [55]. Han et al. in 2006 demonstrated that B cells contribute to periodontal bone loss in the absence of T cells through production of RANKL [63]. Bone resorption and formation are regulated by the relative concentrations of RANKL, RANKL receptor RANK on osteoclast precursor cells and the soluble decoy receptor OPG. When RANKL expression is enhanced relative to OPG, RANKL is available to bind to RANK on osteoclast precursors, tipping the balance to favor activation of osteoclast formation and bone resorption [49]. he binding of RANKL to osteoclast precursors occurs at a stage when hematopoietic stem cells have diferentiated from the colony forming unit for granulocytes and macrophages to the colony forming unit for macrophages (CFU-M). Binding of RANKL to RANK on CFU-M in the presence of macrophage colony stimulating factor induces diferentiation of preosteoclast into a multinucleated cell that becomes a mature osteoclast, which then resorbs bone [65]. When OPG concentrations are high relative to RANKL expression, OPG binds RANKL, inhibiting it to bind to RANK. Preventing the binding of RANKL to RANK leads to reduced formation of osteoclasts and apoptosis of preexisting osteoclasts [49]. Jin et al. in 2007 conducted a study in which rats were administered subcutaneously an OPG-Fc fusion protein to bloc RANK ligand. Compared to the controls, reduced osteoclastogenesis and signiicant preservation of the alveolar bone volume was observed in among the OPG-Fc treated rats [64]. Leiwiecki in 2009 demonstrated that treatment with Denosumab, a human monoclonal antibody speciic for RANKL reduces the risk for fractures and increases the bone mineral density in post-menopausal women. It also inhibits osteoclast-mediated damage caused by rheumatoid arthritis [66]. he studies discussed above have provided valuable insights into the role of inlammation or host response in the pathogenesis of periodontal disease. he studies have unequivocally demonstrated that over ampliication of the immune system releases a host of pro-inlammatory cytokines and mediators that can lead to osteoclastogenesis. Also, these inlammatory mediators can stimulate the release of RANK ligand and thereby lead to bone resorption. he Assessment of RANKL/OPG Ratio in the Severity of Periodontitis A number of clinical studies have investigated the concentrations Study Healthy Gingivitis Mild perio Moderate perio Chronic perio Generalized Chronic with Conclusion subjects (n) subjects (n) subjects (n) subjects (n) subjects (n) aggressive severe immunosuppressant subjects (n) subjects (n) Bostanci et al. (GCF) [68] 21 22 28 25 11 GCF RANKL &OPG were oppositely regulated in periodontitis groups. Bostanci et al. Gingival tissue [69] 9 8 11 12 10 RANKL/OPG ratio increased in all periodontitis groups. Lu et al. (GCF and gingiva) [6] 4 20 Mogi et al. (GCF) [70] 28 27 GCF RANKL, but not OPG was elevated in periodontitis groups. 58 47 RANKL/OPG ratio was signiicantly elevated in periodontitis groups. 27 25 RANKL/OPG was elevated in periodontitis groups. Liu et al. (Gingival tissue) [71] 6 Kawai et al. (gingiva and blood) [72] 12 32 sRANKL, but not OPG was signiicantly higher in periodontitis gropus. Wara-aswapati et al. (gingiva and plaque) [73] 15 15 RANKL/OPG ratio was signiicantly higher in perioidontitis groups Garlet et al. (gingival tissue) [74] 10 Nagasawa et al. (gingival tissue) [75] 2 7 20 16 RANKL/OPG and MMP/TIMP expression determined disease progression/severity 30 OPG is induced by LPSstimulated gingival ibroblast. sRANKL: Soluble Receptor Activator of Nuclear Factor-Kappa B Ligand; TIMP: Tissue Inhibitors of Metalloproteinases; LPS: Lipopolysaccharides; perio: Periodontitis Table 1: Summary of human studies evaluating the RANKL and OPG in Periodontal Disease. J Clin Cell Immunol Innate Response to Infectious Diseases ISSN:2155-9899 JCCI, an open access journal Citation: Srinivasan PC (2013) The Role of Inlammatory Cytokines and the RANKL-RANK-OPG Molecular Triad in Periodontal Bone Loss-A Review. J Clin Cell Immunol S13: 007. doi:10.4172/2155-9899.S13-007 Page 5 of 8 of RANKL and OPG in the gingival crevicular luid of individuals with periodontitis to determine the RANKL/OPG ratio. Table 1 summarizes the human studies evaluating the RANKL and OPG levels in periodontal disease [67]. With a net increase in the ratio of RANKL/OPG in gingiva and crevicular luid associated with bone loss and with the severity of periodontal disease, the possibility of interference with the RANK/ RANKL/OPG axis may ofer novel therapeutic outcomes. he desired outcome would be an increase in OPG or a decrease in RANKL that brings the OPG/RANKL ratio to a balance where bone formation is equal to bone resorption. A summary of animal studies in which osteoprotegerin fusion protein (OPG-Fc) and other inhibitors of RANK-mediated osteoclastogenesis are presented in Table 2 [67]. hus the inference from the above mentioned animal studies is, therapeutic modalities which interfere with the RANK-RANKL-OPG axis will have a protective efect on osteoclastogenesis and periodontal bone loss. Role of Cytokines in Bone Uncoupling Bone is resorbed by osteoclasts, following which new bone is laid down by osteoblasts in the resorption lacunae. Under physiologic conditions, the two activities are coupled, i.e., the amount of bone formed by osteoblasts is equal to that resorbed by osteoclasts. In pathologic processes like periodontal disease and osteoporosis the two processes are uncoupled i.e., there is deicient bone formation following resorption [80]. he inlammatory process that leads to osteoclastogenesis and bone resorption may also be responsible for the failure to form adequate amount of new bone i.e., inlammation causes uncoupling of bone formation following bone resorption [8]. Al-Masahat et al. in 2006 and Liu et al. in 2006 stated that prolonged inlammation in diabetic animals interferes with bone formation in the periodontium following an episode of bone resorption. he prolonged inlammation may stimulate the death of the osteoblasts [81,82]. Application of cytokines like IL-1 beta and TNF-alpha in vivo not only stimulates bone resorption but limits bone formation by inhibiting the coupling process (Bertolini et al. Nyugen et al.) [83,84]. Osteoblast survival is a key factor in bone formation. A study by Diarra and colleagues reported that TNF-alpha stimulates production of Dickkopf-1 (DKK-1), which suppresses bone formation by inhibiting the WNT (wingless WNT/ beta catenin) pathway. DKK-1, a negative regulator of WNT pathway is up-regulated by TNF stimulation through TNF-1 receptor and P38 MAPK (mitogen-activating protein kinase) signaling. he up-regulated DKK-1 not only promotes bone resorption but also blocks bone Study Method Study Method Jin et al. [64] Systemic delivery of rhOPG-Fc Teng et al. [55] Intraperitoneal injection of srOPG-Fc Valverde et al. [76] Subcutaneous kaliotoxin, K+-channel blocker T cells. Kawai et al. [77] Intraperitoneal injection of OPG-Fc Mahamed et al. [78] Intraperitoneal injection of hu-OPG-Fc Rogers et al. [79] Oral gavage of SD282, a p38 MAPK inhibitor Assuma et al. [14] Intrapapillary injection of TNF-alpha and IL-1 antagonists. rhOPG-Fc: Human recombinant osteoprotegerin fusion protein; MAPK: MitogenActivated Protein Kinase; SFRP1: Secreted Frizzled-related Protein 1; hOPGFc: Human Osteoprotegerin fusion protein; srOPG-Fc: soluble recombinant Osteoprotegerin fusion protein; huOPG-Fc: human osteoprotegerin fusion protein; SD282: an indole 5-carboxamide selective p38* MAPK inhibitor (Scois, Fremont, CA). (David L Cochran) Table 2: Summary of animal interventional trials of periodontal disease. J Clin Cell Immunol Figure 1: Schematic illustration depicting the role of inlammatory mediators stimulating osteoclastogenesis and uncoupling of bone leading to alveolar bone loss in periodontal disease. formation and repair in the diseased joint [85]. hus, inlammatory cytokines like TNF-alpha can limit bone formation by inhibiting osteoblast diferentiation. In addition, the pro-inlammatory cytokines may directly stimulate osteoblast or osteoblast precursor apoptosis or indirectly afect it by stimulating expression of Fas, a potent apoptotic mediator [86]. Periodontal ligament cells are an important source of osteoblast precursors. TNF-alpha induced apoptosis of periodontal ligament cells may afect the pool of osteoblast precursors [87]. Another mechanism for uncoupling is the reduced function of osteoblasts mediated by diminished production of bone matrix proteins. A study by Centrella et al. in 1988 showed that TNF-alpha reduces collagen production and alkaline phosphatase activity in cells obtained from fetal rat parietal bone [88]. TNF-alpha and TNF-beta induce a twofold to three-fold reduction in synthesis of non-collagen bone matrix proteins like osteocalcin by osteoblasts [89]. Eguchi et al. stated that TNF speciic inhibitor, etanercept, promotes BMP-2 induced ectopic bone formation when applied systemically or locally in vivo, thereby improving the coupling process [90]. hus evidence from the literature has unequivocally established the negative impact of the inlammatory process on bone coupling. he net bone loss observed in periodontitis is due to the cumulative efect of inlammation-induced bone loss and the uncoupling of bone resorption and bone formation (Figure 1). Innate Response to Infectious Diseases ISSN:2155-9899 JCCI, an open access journal Citation: Srinivasan PC (2013) The Role of Inlammatory Cytokines and the RANKL-RANK-OPG Molecular Triad in Periodontal Bone Loss-A Review. J Clin Cell Immunol S13: 007. doi:10.4172/2155-9899.S13-007 Page 6 of 8 Conclusion Periodontal diseases are chronic inlammatory disorders that alict the supporting structures of the teeth. It is widely recognized that bacteria initiate periodontal diseases. he host responds to this bacterial attack by mounting an immuno-inlammatory response. he host response is essential to ward of the bacterial attack and prevent the systemic dissemination of infection. But in the process, the inlammatory response can also cause tissue destruction and alveolar bone loss. Prolonged inlammation and ampliication of the inlammatory response releases a wide spectrum of pro-inlammatory cytokines and mediators. he cytokines and pro-inlammatory mediators propagate the inlammatory process and the “inlammatory front” advances to the alveolar bone. Alveolar bone loss is the cardinal sign of periodontitis. Experimental periodontitis studies have shown that cytokines like IL-1 and TNF-alpha can lead to alveolar bone loss. hese cytokines can also induce osteoclastogenesis via the RANKLRANK-OPG pathway. IL-1 and TNF-alpha also have a negative impact on bone coupling. he net bone loss seen in periodontitis is due to the cumulative efect of inlammation-induced bone loss and the uncoupling of bone formation and bone resorption. his intricate relationship between inlammation and bone metabolism has led to a new ield of science termed “osteoimmunology.” Extensive research in ield of bone biology has provided valuable insights into pathogenesis of periodontal disease. Inlammation is now recognized as the central component of periodontal disease. Better understanding of the disease process will pave the way for adopting novel treatment approaches and thereby improve clinical outcomes. herapeutic agents antagonistic to the inlammatory mediators or agents which block RANK ligand may be useful adjuncts to the conventional periodontal treatment procedures. 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J Clin Cell Immunol S13: 007. doi:10.4172/2155-9899.S13-007 This article was originally published in a special issue, entitled: “Innate Response to Infectious Diseases”, Edited by Dr. Anshu Agrawal, University of California Irvine, USA J Clin Cell Immunol • 250 Open Access Journals • 20,000 editorial team • 21 days rapid review process • Quality and quick editorial, review and publication processing • Indexing at PubMed (partial), Scopus, EBSCO, Index Copernicus and Google Scholar etc • Sharing Option: Social Networking Enabled • Authors, Reviewers and Editors rewarded with online Scientiic Credits • Better discount for your subsequent articles Submit your manuscript at: www.editorialmanager.com/clinicalgroup Innate Response to Infectious Diseases ISSN:2155-9899 JCCI, an open access journal