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1.  Bis-Enoxacin Blocks Rat Alveolar Bone Resorption from Experimental Periodontitis 
PLoS ONE  2014;9(3):e92119.
Periodontal diseases are multifactorial, caused by polymicrobial subgingival pathogens, including Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. Chronic periodontal infection results in inflammation, destruction of connective tissues, periodontal ligament, and alveolar bone resorption, and ultimately tooth loss. Enoxacin and a bisphosphonate derivative of enoxacin (bis-enoxacin) inhibit osteoclast formation and bone resorption and also contain antibiotic properties. Our study proposes that enoxacin and/or bis-enoxacin may be useful in reducing alveolar bone resorption and possibly bacterial colonization. Rats were infected with 109 cells of polymicrobial inoculum consisting of P. gingivalis, T. denticola, and T. forsythia, as an oral lavage every other week for twelve weeks. Daily subcutaneous injections of enoxacin (5 mg/kg/day), bis-enoxacin (5, 25 mg/kg/day), alendronate (1, 10 mg/kg/day), or doxycycline (5 mg/day) were administered after 6 weeks of polymicrobial infection. Periodontal disease parameters, including bacterial colonization/infection, immune response, inflammation, alveolar bone resorption, and systemic spread, were assessed post-euthanasia. All three periodontal pathogens colonized the rat oral cavity during polymicrobial infection. Polymicrobial infection induced an increase in total alveolar bone resorption, intrabony defects, and gingival inflammation. Treatment with bis-enoxacin significantly decreased alveolar bone resorption more effectively than either alendronate or doxycycline. Histologic examination revealed that treatment with bis-enoxacin and enoxacin reduced gingival inflammation and decreased apical migration of junctional epithelium. These data support the hypothesis that bis-enoxacin and enoxacin may be useful for the treatment of periodontal disease.
doi:10.1371/journal.pone.0092119
PMCID: PMC3956892  PMID: 24638087
2.  MAPK Usage in Periodontal Disease Progression 
Journal of Signal Transduction  2012;2012:308943.
In periodontal disease, host recognition of bacterial constituents, including lipopolysaccharide (LPS), induces p38 MAPK activation and subsequent inflammatory cytokine expression, favoring osteoclastogenesis and increased net bone resorption in the local periodontal environment. In this paper, we discuss evidence that the p38/MAPK-activated protein kinase-2 (MK2) signaling axis is needed for periodontal disease progression: an orally administered p38α inhibitor reduced the progression of experimental periodontal bone loss by reducing inflammation and cytokine expression. Subsequently, the significance of p38 signaling was confirmed with RNA interference to attenuate MK2-reduced cytokine expression and LPS-induced alveolar bone loss. MAPK phosphatase-1 (MKP-1), a negative regulator of MAPK activation, was also critical for periodontal disease progression. In MPK-1-deficient mice, p38-sustained activation increased osteoclast formation and bone loss, whereas MKP-1 overexpression dampened p38 signaling and subsequent cytokine expression. Finally, overexpression of the p38/MK2 target RNA-binding tristetraprolin (TTP) decreased mRNA stability of key inflammatory cytokines at the posttranscriptional level, thereby protecting against periodontal inflammation. Collectively, these studies highlight the importance of p38 MAPK signaling in immune cytokine production and periodontal disease progression.
doi:10.1155/2012/308943
PMCID: PMC3270463  PMID: 22315682
3.  Role of periodontal pathogenic bacteria in RANKL-mediated bone destruction in periodontal disease 
Journal of Oral Microbiology  2010;2:10.3402/jom.v2i0.5532.
Accumulated lines of evidence suggest that hyperimmune responses to periodontal bacteria result in the destruction of periodontal connective tissue and alveolar bone. The etiological roles of periodontal bacteria in the onset and progression of periodontal disease (PD) are well documented. However, the mechanism underlying the engagement of periodontal bacteria in RANKL-mediated alveolar bone resorption remains unclear. Therefore, this review article addresses three critical subjects. First, we discuss earlier studies of immune intervention, ultimately leading to the identification of bacteria-reactive lymphocytes as the cellular source of osteoclast-induction factor lymphokine (now called RANKL) in the context of periodontal bone resorption. Next, we consider (1) the effects of periodontal bacteria on RANKL production from a variety of adaptive immune effector cells, as well as fibroblasts, in inflamed periodontal tissue and (2) the bifunctional roles (upregulation vs. downregulation) of LPS produced from periodontal bacteria in a RANKL-induced osteoclast-signal pathway. Future studies in these two areas could lead to new therapeutic approaches for the management of PD by down-modulating RANKL production and/or RANKL-mediated osteoclastogenesis in the context of host immune responses against periodontal pathogenic bacteria.
doi:10.3402/jom.v2i0.5532
PMCID: PMC3084575  PMID: 21523224
periodontal pathogenic bacteria; RANKL; bone resorption; osteoimmunology
4.  Osteoporosis, jawbones and periodontal disease 
The association between osteoporosis and jawbones remains an argument of debate. Both osteoporosis and periodontal diseases are bone resorptive diseases; it has been hypothesized that osteoporosis could be a risk factor for the progression of periodontal disease and vice versa. Hypothetical models linking the two conditions exist: in particular, it is supposed that the osteoporosis-related bone mass density reduction may accelerate alveolar bone resorption caused by periodontitis, resulting in a facilitated periodontal bacteria invasion. Invading bacteria, in turn, may alter the normal homeostasis of bone tissue, increasing osteoclastic activity and reducing local and systemic bone density by both direct effects (release of toxins) and/or indirect mechanisms (release of inflammatory mediators). Current evidence provides conflicting results due to potential biases related to study design, samples size and endpoints. The aim of this article is to review and summarize the published literature on the associations between osteoporosis and different oral conditions such as bone loss in the jaws, periodontal diseases, and tooth loss. Further well-controlled studies are needed to better elucidate the inter-relationship between systemic and oral bone loss and to clarify whether dentists could usefully provide early warning for osteoporosis risk.
Key words:Osteoporosis, periodontitis, oral bone loss, tooth loss, edentulism, bone mineral density.
doi:10.4317/medoral.18298
PMCID: PMC3548653  PMID: 23229255
5.  Magnolol Ameliorates Ligature-Induced Periodontitis in Rats and Osteoclastogenesis: In Vivo and In Vitro Study 
Periodontal disease characterized by alveolar bone resorption and bacterial pathogen-evoked inflammatory response has been believed to have an important impact on human oral health. The aim of this study was to evaluate whether magnolol, a main constituent of Magnolia officinalis, could inhibit the pathological features in ligature-induced periodontitis in rats and osteoclastogenesis. The sterile, 3–0 (diameter; 0.2 mm) black braided silk thread, was placed around the cervix of the upper second molars bilaterally and knotted medially to induce periodontitis. The morphological changes around the ligated molars and alveolar bone were examined by micro-CT. The distances between the amelocemental junction and the alveolar crest of the upper second molars bilaterally were measured to evaluate the alveolar bone loss. Administration of magnolol (100 mg/kg, p.o.) significantly inhibited alveolar bone resorption, the number of osteoclasts on bony surface, and protein expression of receptor activator of nuclear factor-κB ligand (RANKL), a key mediator promoting osteoclast differentiation, in ligated rats. Moreover, the ligature-induced neutrophil infiltration, expression of inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase (MMP)-1 and MMP-9, superoxide formation, and nuclear factor-κB activation in inflamed gingival tissues were all attenuated by magnolol. In the in vitro study, magnolol also inhibited the growth of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans that are key pathogens initiating periodontal disease. Furthermore, magnolol dose dependently reduced RANKL-induced osteoclast differentiation from RAW264.7 macrophages, tartrate-resistant acid phosphatase (TRAP) activity of differentiated cells accompanied by a significant attenuation of resorption pit area caused by osteoclasts. Collectively, we demonstrated for the first time that magnolol significantly ameliorates the alveolar bone loss in ligature-induced experimental periodontitis by suppressing periodontopathic microorganism accumulation, NF-κB-mediated inflammatory mediator synthesis, RANKL formation, and osteoclastogenesis. These activities support that magnolol is a potential agent to treat periodontal disease.
doi:10.1155/2013/634095
PMCID: PMC3618931  PMID: 23573141
6.  Relationship Between Osteoporosis and Periodontal Disease: Review of the Literature 
Objective
Osteoporosis is a skeletal disease characterized by reduction in bone mass and micro architectural changes in the bone, which leads to increased bone fragility. The gold standard for the diagnosis of osteoporosis is the measurement of bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA). Periodontal disease is a chronic destructive disease which can occur in adults, young people and children. Periodontal pathogens cause inflammation of the gingiva which is called gingivitis. When periodontal tissue destruction and alveolar bone loss happen, it is called periodontitis. Since both osteoporosis and periodontal diseases are bone destructive diseases, it has been hypothesized that osteoporosis could be a risk factor for the progression of periodontal disease. The aim of this study is to review the articles assessing the relationship between osteoporosis and periodontitis
Materials and Methods:
In this review, articles were selected from PubMed between January of 1998 and June 2010. Amongst 508 articles identified from the electronic search, 17 articles were selected for a full-text reading based on the inclusion and exclusion criteria.
Results:
Among the 17 studies focused on, 11 studies showed a positive relation between osteoporosis and periodontal disease and the six remaining studies found no significant relation between osteoporosis and periodontal disease.
Conclusion:
These data indicate a greater propensity to lose alveolar bone in subjects with osteoporosis, especially in subjects with preexisting periodontitis. This would indicate that osteoporosis or low systemic BMD should be considered a risk factor for periodontal disease progression.
PMCID: PMC3536461  PMID: 23323188
Periodontitis; Tooth Loss; Bone Density; Osteoporosis
7.  Porphyromonas gingivalis GroEL Induces Osteoclastogenesis of Periodontal Ligament Cells and Enhances Alveolar Bone Resorption in Rats 
PLoS ONE  2014;9(7):e102450.
Porphyromonas gingivalis is a major periodontal pathogen that contains a variety of virulence factors. The antibody titer to P. gingivalis GroEL, a homologue of HSP60, is significantly higher in periodontitis patients than in healthy control subjects, suggesting that P. gingivalis GroEL is a potential stimulator of periodontal disease. However, the specific role of GroEL in periodontal disease remains unclear. Here, we investigated the effect of P. gingivalis GroEL on human periodontal ligament (PDL) cells in vitro, as well as its effect on alveolar bone resorption in rats in vivo. First, we found that stimulation of PDL cells with recombinant GroEL increased the secretion of the bone resorption-associated cytokines interleukin (IL)-6 and IL-8, potentially via NF-κB activation. Furthermore, GroEL could effectively stimulate PDL cell migration, possibly through activation of integrin α1 and α2 mRNA expression as well as cytoskeletal reorganization. Additionally, GroEL may be involved in osteoclastogenesis via receptor activator of nuclear factor κ-B ligand (RANKL) activation and alkaline phosphatase (ALP) mRNA inhibition in PDL cells. Finally, we inoculated GroEL into rat gingiva, and the results of microcomputed tomography (micro-CT) and histomorphometric assays indicated that the administration of GroEL significantly increased inflammation and bone loss. In conclusion, P. gingivalis GroEL may act as a potent virulence factor, contributing to osteoclastogenesis of PDL cells and resulting in periodontal disease with alveolar bone resorption.
doi:10.1371/journal.pone.0102450
PMCID: PMC4109931  PMID: 25058444
8.  Cytokine-Mediated Bone Destruction in Rheumatoid Arthritis 
Journal of Immunology Research  2014;2014:263625.
Bone homeostasis, which involves formation and resorption, is an important process for maintaining adequate bone mass in humans. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and bone loss, leading to joint destruction and deformity, and is a representative disease of disrupted bone homeostasis. The bone loss and joint destruction are mediated by immunological insults by proinflammatory cytokines and various immune cells. The connection between bone and immunity has been intensely studied and comprises the emerging field of osteoimmunology. Osteoimmunology is an interdisciplinary science investigating the interplay between the skeletal and the immune systems. The main contributors in osteoimmunology are the bone effector cells, such as osteoclasts or osteoblasts, and the immune cells, particularly lymphocytes and monocytes. Physiologically, osteoclasts originate from immune cells, and immune cells regulate osteoblasts and vice versa. Pathological conditions such as RA might affect these interactions, thereby altering bone homeostasis, resulting in the unfavorable outcome of bone destruction. In this review, we describe the osteoclastogenic roles of the proinflammatory cytokines and immune cells that are important in the pathophysiology of RA.
doi:10.1155/2014/263625
PMCID: PMC4176903  PMID: 25295284
9.  Osteoimmunology and osteoporosis 
The concept of osteoimmunology is based on growing insight into the links between the immune system and bone at the anatomical, vascular, cellular, and molecular levels. In both rheumatoid arthritis (RA) and ankylosing spondylitis (AS), bone is a target of inflammation. Activated immune cells at sites of inflammation produce a wide spectrum of cytokines in favor of increased bone resorption in RA and AS, resulting in bone erosions, osteitis, and peri-inflammatory and systemic bone loss. Peri-inflammatory bone formation is impaired in RA, resulting in non-healing of erosions, and this allows a local vicious circle of inflammation between synovitis, osteitis, and local bone loss. In contrast, peri-inflammatory bone formation is increased in AS, resulting in healing of erosions, ossifying enthesitis, and potential ankylosis of sacroiliac joints and intervertebral connections, and this changes the biomechanical competence of the spine. These changes in bone remodeling and structure contribute to the increased risk of vertebral fractures (in RA and AS) and non-vertebral fractures (in RA), and this risk is related to severity of disease and is independent of and superimposed on background fracture risk. Identifying patients who have RA and AS and are at high fracture risk and considering fracture prevention are, therefore, advocated in guidelines. Local peri-inflammatory bone loss and osteitis occur early and precede and predict erosive bone destruction in RA and AS and syndesmophytes in AS, which can occur despite clinically detectable inflammation (the so-called 'disconnection'). With the availability of new techniques to evaluate peri-inflammatory bone loss, osteitis, and erosions, peri-inflammatory bone changes are an exciting field for further research in the context of osteoimmunology.
doi:10.1186/ar3375
PMCID: PMC3308061  PMID: 21996023
10.  RNAi-Mediated Silencing of Atp6i and Atp6i Haploinsufficiency Prevents Both Bone Loss and Inflammation in a Mouse Model of Periodontal Disease 
PLoS ONE  2013;8(4):e58599.
Periodontal disease affects about 80% of adults in America, and is characterized by oral bacterial infection-induced gingival inflammation, oral bone resorption, and tooth loss. Periodontitis is also associated with other diseases such as rheumatoid arthritis, diabetes, and heart disease. Although many efforts have been made to develop effective therapies for this disease, none have been very effective and there is still an urgent need for better treatments and preventative strategies. Herein we explored for the first time the possibility that adeno-associated virus (AAV)-mediated RNAi knockdown could be used to treat periodontal disease with improved efficacy. For this purpose, we used AAV-mediated RNAi knockdown of Atp6i/TIRC7 gene expression to target bone resorption and gingival inflammation simultaneously. Mice were infected with the oral pathogen Porphyromonas gingivalis W50 (P. gingivalis) in the maxillary periodontium to induce periodontitis. We found that Atp6i depletion impaired extracellular acidification and osteoclast-mediated bone resorption. Furthermore, local injection of AAV-shRNA-Atp6i/TIRC7 into the periodontal tissues in vivo protected mice from P. gingivalis infection-stimulated bone resorption by >85% and decreased the T-cell number in periodontal tissues. Notably, AAV-mediated Atp6i/TIRC7 knockdown also reduced the expression of osteoclast marker genes and inflammation-induced cytokine genes. Atp6i+/− mice with haploinsufficiency were similarly protected from P. gingivalis infection-stimulated bone loss and gingival inflammation. This suggests that AAV-shRNA-Atp6i/TIRC7 therapeutic treatment may significantly improve the health of millions who suffer from P. gingivalis-mediated periodontal disease.
doi:10.1371/journal.pone.0058599
PMCID: PMC3618217  PMID: 23577057
11.  Bone Regeneration in Odontostomatology 
Maxillary edentulism, together with periodontal disease, is the condition that most frequently induces disruption of alveolar bone tissue. Indeed, the stimulus of the periodontal ligament is lost and the local bone tissue becomes subject to resorption processes that, in the six months following the loss of the tooth, result in alveolar defects or more extensive maxillary atrophy. In both cases, loss of vestibular cortical bone is followed by reduction in the vertical dimension of the alveolar process, producing effects that upset the morphology of the three-dimensional relations between the dental arches. Maintenance, or restoration, of sufficient bone volume to withstand prosthetic loading and the insertion of an endosseous implant, demands the implementation of operating protocols that bring about bone regeneration in the defect sites. Given the biological principles involved, this requires the implementation of osteogenesis, osteoinduction and osteoconduction protocols.
Osteogenesis is the synthesis of new bone by autologous cells that remain viable, given the capacity of the grafted material to become part of the newly forming bone tissue; osteoinduction is based on the capacity of the grafted material to induce the migration, proliferation and phenotypic conversion, into bone-producing cells, of multipotent undifferentiated cells derived from connective tissue or bone marrow; osteoconduction, meanwhile, provides three-dimensional support and guidance to osteoblast precursors within the defect. The operating procedures implemented take into account the size and morphology of the defect, for the restoration of which guided repair or an out-and-out regenerative protocol may be sufficient. Guided repair exploits the principle of resorption/replacement of the biomaterial with newly-formed bone and consists of restoring the lost bone tissue through the implantation of different, osteointegrative biomaterials. This type of repair requires the application of biocompatible osteoconductors which will gradually be absorbed and replaced by newly formed tissue. Instead, the clinical-surgical basis of bone regeneration is: guided bone regeneration (GBR), the use of growth factors and the application of grafts/osteointegrative materials. GBR, through the use of membranes (resorbable or non-resorbable) allows the filling of a defect, “guiding” the growth only of the osteogenic lines and preventing the invasion of non-osteogenic tissues that compete with the bone. This objective is achieved also thanks to the capacity of the membranes to serve as a filter, thereby strengthening the osteocompetent lines and, at the same time, keeping epithelial cells away. The clinical use of GBR, partly on account of its predictable results, is now very widespread. The growth factors used in bone regeneration are glycoproteins which exert autocrine and paracrine effects on the primordial cells in the site. One of these factors, plasma-rich protein (PRP), is an autologous source of growth factors; obtained by separating and concentrating the platelets in a small volume of plasma, it is immediately utilisable in the surgical site. As regards the osteointegrative materials we can distinguish between autologous, homologous, heterologous, and alloplastic grafts. Of these, autologous bone is the gold standard as it has osteogenic, osteoinductive, and osteoconductive properties and, being fresh, keeps osteoblasts viable. Depending on the size of the defect to be treated, harvesting is from endoral or extraoral sites (calvaria, iliac crest, tibia). The harvested material conserves the embryological characteristics of the site of origin: this principle is reflected in the bone density that develops in the regenerated site. Homologous bone supplied by tissue banks in various formulations is an osteoconductive and partially osteoinductive material that guarantees good mechanical properties even in large defects. Heterologous bone of bovine or equine origin is a carbonate-rich non-stoichiometric apatite. Despite showing low resorption, it does not withstand traction or masticatory loading. Alloplastic materials are osteoconductive materials showing different degrees of resorption; they have biomechanical properties and the speed of their resorption varies, depending on their chemical and stoichiometric formulation. The purpose of bone regeneration thus obtained is to allow the insertion of a titanium implant in the site of the regeneration. This alloplastic implant, whose rough and porous surface allows integration with the bone tissue, will support the prosthesis subsequently applied.
PMCID: PMC3213819
12.  Biochemical markers as predictors of bone remodelling in dental disorders: a narrative description of literature 
Summary
Osteoporosis is a systemic disease in which the skeletal condition is characterized by a decreased mass of normally mineralized bone, due to an augmentation of bone resorption processes. Bone biomarkers serum are used for the diagnosis. On the other hand the main cause of the resorption in the bone jaws are periodontitis, inflammatory cysts, developmental cysts, odontogenic neoplasms. Periodontal diseases can be localized to a single site of the jaws or can affect all the teeth, with a massive bone resorption. The cysts are classified in developmental and inflammatory. They caused a local bone resorption in the jaws. Keratocystic odontogenic tumor produces a large bone resorption for its local aggressive nature. Their diagnosis is clinical and radiological.
The aim of our review is to find a correlation between bone biomarkers serum and periodontitis, inflammatory cists, developmental cysts, odontogenetic neoplasms.
The RANK/RANKL/OPG system is the most studied not only in osteoporosis but also in the periodontitis, inflammatory cysts, developmental cysts, odontogenic neoplasms. In the last years osteoimmunology was used to study the periodontal disease progression, because the immunity cells start the bone resorption processes.
A lot of studies analyze the biomarkers present in the biofluids, as saliva and gingival crevicular fluid, but not the correlation with serum biomarkers.
Future studies must be organized to deepen the correlation between bone biomarkers and bone jaws resorption and to allow diagnosis and prognosis of periodontitis, inflammatory cysts, developmental cysts, odontogenic neoplasms.
PMCID: PMC3476527  PMID: 23087720
osteoporosis; periodontitis; odontogenic cyst; serum marker; Rankl
13.  The role of RANK ligand/osteoprotegerin in rheumatoid arthritis 
In the complex system of bone remodeling, the receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) pathway is the coupling factor between bone formation and bone resorption. RANKL binds to the RANK receptor of pre-osteoclasts and mature osteoclasts and stimulates their activation and differentiation. The production of RANKL/OPG by osteoblasts is influenced by hormones, growth factors and cytokines, which each have a different effect on the production of RANKL and OPG. Ultimately, the balance between RANKL and OPG determines the degree of proliferation and activity of the osteoclasts. In rheumatoid arthritis (RA), bone erosions are the result of osteoclastic bone resorption at the sites of synovitis, where RANKL expression is also found. Furthermore, magnetic resonance imaging (MRI) bone edema in RA indicates the presence of active inflammation within bone and the presence of osteitis, which is also associated with the expression of RANKL. Bone loss has been documented in the cortical and trabecular bone in the joints of the hand of RA patients. Both synovitis and periarticular bone involvement (osteitis and bone loss) are essential components of RA: they occur early in the disease and both are predictive for the occurrence and progression of bone damage. RANKL knockout mice and mice treated with OPG did not develop focal bone loss, in spite of persistent joint inflammation. Inhibition of osteoclasts by denosumab, a humanized antibody that selectively binds RANKL, has revealed in patients with RA that the occurrence of erosions and periarticular bone loss can be halted, however without affecting synovial inflammation. This disconnect between inflammation and bone destruction opens new ways to separately focus treatment on inflammation and osteoclastogenesis for preventing and/or minimizing the connection between joints and subchondral bone and bone marrow.
doi:10.1177/1759720X12438080
PMCID: PMC3403250  PMID: 22859921
RANK ligand; osteoprotegerin; rheumatoid arthritis; bone erosions; osteitis; bone loss
14.  Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection  
Periodontitis, a prime cause of tooth loss in humans, is implicated in the increased risk of systemic diseases such as heart failure, stroke, and bacterial pneumonia. The mechanisms by which periodontitis and antibacterial immunity lead to alveolar bone and tooth loss are poorly understood. To study the human immune response to specific periodontal infections, we transplanted human peripheral blood lymphocytes (HuPBLs) from periodontitis patients into NOD/SCID mice. Oral challenge of HuPBL-NOD/SCID mice with Actinobacillus actinomycetemcomitans, a well-known Gram-negative anaerobic microorganism that causes human periodontitis, activates human CD4+ T cells in the periodontium and triggers local alveolar bone destruction. Human CD4+ T cells, but not CD8+ T cells or B cells, are identified as essential mediators of alveolar bone destruction. Stimulation of CD4+ T cells by A. actinomycetemcomitans induces production of osteoprotegerin ligand (OPG-L), a key modulator of osteoclastogenesis and osteoclast activation. In vivo inhibition of OPG-L function with the decoy receptor OPG diminishes alveolar bone destruction and reduces the number of periodontal osteoclasts after microbial challenge. These data imply that the molecular explanation for alveolar bone destruction observed in periodontal infections is mediated by microorganism-triggered induction of OPG-L expression on CD4+ T cells and the consequent activation of osteoclasts. Inhibition of OPG-L may thus have therapeutic value to prevent alveolar bone and/or tooth loss in human periodontitis.
This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 106:R59–R67 (2000).
PMCID: PMC3102542  PMID: 10995794
15.  Antibody to Receptor Activator of NF-κB Ligand Ameliorates T Cell-Mediated Periodontal Bone Resorption ▿  
Infection and Immunity  2010;79(2):911-917.
Activated T and B lymphocytes in periodontal disease lesions express receptor activator of NF-κB ligand (RANKL), which induces osteoclastic bone resorption. The objective of this study was to evaluate the effects of anti-RANKL antibody on periodontal bone resorption in vitro and in vivo. Aggregatibacter actinomycetemcomitans outer membrane protein 29 (Omp29) and A. actinomycetemcomitans lipopolysaccharide (LPS) were injected into 3 palatal gingival sites, and Omp29-specific T clone cells were transferred into the tail veins of rats. Rabbit anti-RANKL IgG antibody or F(ab′)2 antibody fragments thereof were injected into the palatal sites in each rat (days −1, 1, and 3). Anti-RANKL IgG antibody significantly inhibited soluble RANKL (sRANKL)-induced osteoclastogenesis in vitro, in a dose-dependent manner, but also gave rise to a rat antibody response to rabbit IgG in vivo, with no significant inhibition of periodontal bone resorption detected. Lower doses (1.5 and 0.15 μg/3 sites) of F(ab′)2 antibody were not immunogenic in the context of the experimental model. Periodontal bone resorption was inhibited significantly by injection of the anti-RANKL F(ab′)2 antibody into gingivae. The sRANKL concentrations for the antibody-treated groups were decreased significantly compared to those for the untreated group. Osteoclasts on the alveolar bone surface were also diminished significantly after antibody injection. Gingival sRANKL concentration and bone loss showed a significant correlation with one another in animals receiving anti-RANKL F(ab′)2 antibody. These results suggest that antibody to RANKL can inhibit A. actinomycetemcomitans-specific T cell-induced periodontal bone resorption by blockade and reduction of tissue sRANKL, providing an immunological approach to ameliorate immune cell-mediated periodontal bone resorption.
doi:10.1128/IAI.00944-10
PMCID: PMC3028846  PMID: 21078845
16.  Amelogenins: Multi-Functional Enamel Matrix Proteins and Their Binding Partners 
Amelogenins are the most abundant extracellular matrix proteins secreted by ameloblasts during tooth development and are important for enamel formation. Recently, amelogenins have been detected not only in ameloblasts, which are differentiated from the epithelial cell lineage, but also in other tissues, including mesenchymal tissues at low levels, suggesting that amelogenins possess other functions in these tissues. The therapeutic application of an enamel matrix derivative rich in amelogenins resulted in the regeneration of cementum, alveolar bone, and periodontal ligament (PDL) in the treatment of experimental or human periodontitis, indicating the attractive potential of amelogenin in hard tissue formation. In addition, a full-length amelogenin (M180) and leucine-rich amelogenin peptide (LRAP) regulate cementoblast/PDL cell proliferation and migration in vitro. Interestingly, amelogenin null mice show increased osteoclastogenesis and root resorption in periodontal tissues. Recombinant amelogenin proteins suppress osteoclastogenesis in vivo and in vitro, suggesting that amelogenin is involved in preventing idiopathic root resorption. Amelogenins are implicated in tissue-specific epithelial-mesenchymal or mesenchymal-mesenchymal signaling; however, the precise molecular mechanism has not been characterized.
In this review, we first discuss the emerging evidence for the additional roles of M180 and LRAP as signaling molecules in mesenchymal cells. Next, we show the results of a yeast two-hybrid assay aimed at identifying protein-binding partners for LRAP. We believe that gaining further insights into the signaling pathway modulated by the multifunctional amelogenin proteins will lead to the development of new therapeutic approaches for treating dental diseases and disorders.
PMCID: PMC3732036  PMID: 23914134
amelogenin; yeast two-hybrid; M180; leucine-rich amelogenin peptide(LRAP); signaling molecules
17.  Review of osteoimmunology and the host response in endodontic and periodontal lesions 
Journal of Oral Microbiology  2011;3:10.3402/jom.v3i0.5304.
Both lesions of endodontic origin and periodontal diseases involve the host response to bacteria and the formation of osteolytic lesions. Important for both is the upregulation of inflammatory cytokines that initiate and sustain the inflammatory response. Also important are chemokines that induce recruitment of leukocyte subsets and bone-resorptive factors that are largely produced by recruited inflammatory cells. However, there are differences also. Lesions of endodontic origin pose a particular challenge since that bacteria persist in a protected reservoir that is not readily accessible to the immune defenses. Thus, experiments in which the host response is inhibited in endodontic lesions tend to aggravate the formation of osteolytic lesions. In contrast, bacteria that invade the periodontium appear to be less problematic so that blocking arms of the host response tend to reduce the disease process. Interestingly, both lesions of endodontic origin and periodontitis exhibit inflammation that appears to inhibit bone formation. In periodontitis, the spatial location of the inflammation is likely to be important so that a host response that is restricted to a subepithelial space is associated with gingivitis, while a host response closer to bone is linked to bone resorption and periodontitis. However, the persistence of inflammation is also thought to be important in periodontitis since inflammation present during coupled bone formation may limit the capacity to repair the resorbed bone.
doi:10.3402/jom.v3i0.5304
PMCID: PMC3087239  PMID: 21547019
bacteria; bone; chemokine; cytokine; endodontic lesion; gingivitis; periodontitis; inflammation
18.  Anti-inflammatory Effect of MAPK Phosphatase-1 Local Gene Transfer in Inflammatory Bone Loss 
Gene therapy  2010;18(4):344-353.
Alveolar bone loss associated with periodontal diseases is the result of osteoclastogenesis induced by bacterial pathogens. The mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP- 1) is a critical negative regulator of immune response as a key phosphatase capable of dephosphorylating activated MAPKs. In this study, rat macrophages transduced with recombinant adenovirus (Ad).MKP-1 specifically dephosphorylated activated MAPKs induced by lipopolysaccharide (LPS) compared with control cells. Bone marrow macrophages from MKP-1 knockout (KO) mice exhibited higher interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and select chemokine compared with wild type (WT) mice when stimulated by LPS. In addition, bone marrow cultures from MKP-1 KO mice exhibited significantly more osteoclastogenesis induced by LPS compared with WT mice. Importantly, MKP-1 gene transfer in bone marrow cells of MKP-1 KO mice significantly decreased IL-6, IL-10, TNF-α, chemokine levels and formed fewer osteoclasts induced by LPS compared with control group of cells. Furthermore, MKP-1 gene transfer in an experimental periodontal disease model attenuated bone resorption induced by LPS. Histological analysis confirmed that periodontal tissues transduced with Ad.MKP-1 exhibited less infiltrated inflammatory cells, less osteoclasts and less IL-6 compared with rats of control groups. These studies indicate that MKP-1 is a key therapeutic target to control of inflammation-induced bone loss.
doi:10.1038/gt.2010.139
PMCID: PMC3086452  PMID: 21068780
MKP-1; cytokine; osteoclastogenesis; periodontal disease
19.  Apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis 
The mechanisms underlying the destruction of bone tissue in osteomyelitis are only now being elucidated. While some of the tissue damage associated with osteomyelitis likely results from the direct actions of bacteria and infiltrating leukocytes, perhaps exacerbated by bacterial manipulation of leukocyte survival pathways, infection-induced bone loss predominantly results from an uncoupling of the activities of osteoblasts and osteoclasts. Bacteria or their products can directly increase osteoclast formation and activity, and the inflammatory milieu at sites of infection can further promote bone resorption. In addition, osteoclast activity is critically regulated by osteoblasts that can respond to bacterial pathogens and foster both inflammation and osteoclastogenesis. Importantly, bone loss during osteomyelitis is also brought about by a decline in new bone deposition due to decreased bone matrix synthesis and by increased rates of osteoblast apoptosis. Extracellular bacterial components may be sufficient to reduce osteoblast viability, but the causative agents of osteomyelitis are also capable of inducing continuous apoptosis of these cells by activating intrinsic and extrinsic cell death pathways to further uncouple bone formation and resorption. Interestingly, bacterial internalization appears to be required for maximal osteoblast apoptosis, and cytosolic inflammasome activation may act in concert with autocrine/paracrine death receptor-ligand signaling to induce cell death. The manipulation of apoptotic pathways in infected bone cells could be an attractive new means to limit inflammatory damage in osteomyelitis. However, the mechanism that is the most important in bacterium-induced bone loss has not yet been identified. Furthermore, it remains to be determined whether the host would be best served by preventing osteoblast cell death or by promoting apoptosis in infected cells.
doi:10.3389/fcimb.2013.00101
PMCID: PMC3867676  PMID: 24392356
osteomyelitis; apoptosis; osteoblasts; osteoclasts; inflammation; osteoimmunology; bacterial infection
20.  Study of TNF-α, IL-1β and LPS Levels in the Gingival Crevicular Fluid of a Rat Model of Diabetes Mellitus and Periodontitis 
Disease markers  2013;34(5):295-304.
OBJECTIVE: In this study, we sought to investigate the dynamic changes in the levels of TNF-α, IL-1β and LPS in the gingival crevicular fluid (GCF) in a rat model of diabetes mellitus (DM) and periodontitis (PD). Additionally, we evaluated alveolar bone loss and the histopathological response associated with experimental diabetes mellitus and experimental periodontitis.
METHODS: DM and PD were induced together in 15 rats (group 1) by streptozotocin injection and ligature induction. Periodontitis alone was produced by ligature induction in 15 rats (group 2), diabetes alone was produced by streptozotocin injection in 15 rats (group 3), and fifteen systemically and periodontally healthy rats were used as controls (group 4). The gingival TNF-α, IL-1β and LPS levels were measured by using ELISA method. Periodontal destruction was assessed by measuring the alveolar bone loss. Periodontal inflammation was quantified by histopathological grading in H&E stained samples.
RESULTS: Higher levels of TNF-α, IL1-β and LPS, increased alveolar bone loss and more serve histopathology were found in group 1 compared with group 2, group 3 and group 4 (p < 0.05). The quantities of TNF-α, IL1-β and LPS, the amount of alveolar bone loss and the severity of the histopathological finding were greater in group 2 than group 3 and group 4 (p < 0.05). Group 3 demonstrated higher levels of TNF-α, IL1-β and LPS, increased alveolar bone loss and more serve histopathology than group 4 (p < 0.05). Statistically significant differences were noted between all of the groups.
CONCLUSIONS: These data indicate that DM may lead to enhanced TNF-α, IL1-β and LPS production in the periodontal tissues. The resorption values of alveolar bone and the histological inflammation were more severe in rats with periodontitis and diabetes mellitus than in those with periodontitis alone, diabetes mellitus alone and control rats. Our findings are consistent with the hypothesis that hyperglycemia contributes to the heightened inflammatory response associated with periodontitis.
doi:10.3233/DMA-130974
PMCID: PMC3809972  PMID: 23478270
TNF-α; IL-1β; LPS; GCF; diabetes mellitus; periodontitis; alveolar bone loss; histopathology
21.  Involvement of SOCS3 in Regulation of CD11c+ Dendritic Cell-Derived Osteoclastogenesis and Severe Alveolar Bone Loss ▿  
Infection and Immunity  2009;77(5):2000-2009.
To investigate the role of suppressor of cytokine signaling (SOCS) molecules in periodontal immunity and RANKL-mediated dendritic cell (DC)-associated osteoclastogenesis, we analyzed SOCS expression profiles in CD4+ T cells and the effect of SOCS3 expression in CD11c+ DCs during periodontal inflammation-induced osteoclastogenesis and bone loss in nonobese diabetic (NOD) versus humanized NOD/SCID mice. Our results of ex vivo and in vitro analyses showed that (i) there is significantly higher SOCS3 expression associated with RANKL+ T-cell-mediated bone loss in correlation with increased CD11c+ DC-mediated osteoclastogenesis; (ii) the transfection of CD11c+ DC using an adenoviral vector carrying a dominant negative SOCS3 gene significantly abrogates TRAP and bone-resorptive activity; and (iii) inflammation-induced TRAP expression, bone resorption, and SOCS3 activity are not associated with any detectable change in the expression levels of TRAF6 and mitogen-activated protein kinase signaling adaptors (i.e., Erk, Jnk, p38, and Akt) in RANKL+ T cells. We conclude that SOCS3 plays a critical role in modulating cytokine signaling involved in RANKL-mediated DC-derived osteoclastogenesis during immune interactions with T cells and diabetes-associated severe inflammation-induced alveolar bone loss. Therefore, the development of SOCS3 inhibitors may have therapeutic potential as the target to halt inflammation-induced bone loss under pathological conditions in vivo.
doi:10.1128/IAI.01070-08
PMCID: PMC2681769  PMID: 19255186
22.  Comparative evaluation of serum antioxidant levels in periodontally diseased patients: An interventional study 
Contemporary Clinical Dentistry  2014;5(3):340-344.
Background:
Periodontal disease is an immune-inflammatory disease characterized by connective tissue breakdown, loss of attachment and alveolar bone resorption. In normal physiology, there is a dynamic equilibrium between reactive oxygen species activity and antioxidant defense capacity and when that equilibrium shifts in favor of reactive oxygen species, oxidative stress results. Oxidative stress is thought to play a causative role in the pathogenesis of periodontal diseases. Catalase (CAT) protects cells from hydrogen peroxide generated within them. Even though, CAT is not essential for some cell types under normal conditions, it plays an important role countering the effects of oxidative stress on the cell.
Aim:
This study was designed to estimate and compare the CAT and total antioxidant capacity (TAOC) levels in the serum of periodontitis, gingivitis, and healthy individuals before and after nonsurgical periodontal therapy.
Materials and Methods:
This study was conducted in the Department of Periodontics, A. B. Shetty Memorial Institute of Dental Sciences, Deralakatte, Mangalore. The study was designed as a single blinded interventional study comprising of 75 subjects, inclusive of both sexes and divided into three groups of 25 patients each. Patients were categorized into chronic periodontitis, gingivitis and healthy. The severity of inflammation was assessed by using gingival index and pocket probing depth. Biochemical analysis was done to estimate the TAOC and CAT levels before and after nonsurgical periodontal therapy. Results obtained were then statistically analyzed using ANOVA test and paired t-test.
Results:
The results showed a higher level of serum TAOC and CAT in the healthy group compared with the other groups. The difference was found to be statistically significant (P < 0.0001). The posttreatment levels of TAOC were statistically higher than the pretreatment levels in periodontitis group.
doi:10.4103/0976-237X.137938
PMCID: PMC4147810  PMID: 25191070
Antioxidant defense; catalase; interventional study; periodontitis; total antioxidants
23.  Integrin α5β1-fimbriae binding and actin rearrangement are essential for Porphyromonas gingivalis invasion of osteoblasts and subsequent activation of the JNK pathway 
BMC Microbiology  2013;13:5.
Background
Chronic periodontitis is an infectious disease of the periodontium, which includes the gingival epithelium, periodontal ligament and alveolar bone. The signature clinical feature of periodontitis is resorption of alveolar bone and subsequent tooth loss. The Gram-negative oral anaerobe, Porphyromonas gingivalis, is strongly associated with periodontitis, and it has been shown previously that P. gingivalis is capable of invading osteoblasts in a dose- and time-dependent manner resulting in inhibition of osteoblast differentiation and mineralization in vitro. It is not yet clear which receptors and cytoskeletal components mediate the invasive process, nor how the signaling pathways and viability of osteoblasts are affected by bacterial internalization. This study aimed to investigate these issues using an in vitro model system involving the inoculation of P. gingivalis ATCC 33277 into primary osteoblast cultures.
Results
It was found that binding between P. gingivalis fimbriae and integrin α5β1 on osteoblasts, and subsequent peripheral condensation of actin, are essential for entry of P. gingivalis into osteoblasts. The JNK pathway was activated in invaded osteoblasts, and apoptosis was induced by repeated infections.
Conclusions
These observations indicate that P. gingivalis manipulates osteoblast function to promote its initial intracellular persistence by prolonging the host cell life span prior to its intercellular dissemination via host cell lysis. The identification of molecules critical to the interaction between P. gingivalis and osteoblasts will facilitate the development of new therapeutic strategies for the prevention of periodontal bone loss.
doi:10.1186/1471-2180-13-5
PMCID: PMC3566952  PMID: 23305098
Osteoblasts; Porphyromonas gingivalis; Integrins; Cytoskeleton; Signaling; Apoptosis
24.  LOSS OF DENTIN SIALOPHOSPHOPROTEIN (DSPP) LEADS TO PERIODONTAL DISEASES IN MICE 
Journal of periodontal research  2012;48(2):221-227.
Background and Objective
Dentin sialophosphoprotein (DSPP) and its cleaved products, dentin phosphoprotein (DPP) and dentin sialoprotein (DSP), play important roles in biomineralization. Recently, we observed that DSPP is highly expressed in the alveolar bone and cementum, indicating that this molecule may play an important role in the formation and maintenance of a healthy periodontium, and its deletion may cause increased susceptibility to periodontal diseases. The objective of this investigation was to study the effects of Dspp ablation on periodontal tissues by analyzing Dspp null mice.
Methods
Newborn to 6-month-old Dspp null mice were examined, and the 3-month and 6-month-old Dspp null mice were characterized in detail using X-ray radiography, histology and scanning electron microscopy (backscattered as well as resin-infiltrating). Wild-type mice of the same age groups served as the normal controls.
Results
The Dspp null mice showed a significant loss of alveolar bone and cementum, particularly in the furcation and the interproximal regions of the molars. The alveolar bone appeared more porous while the quantity of cementum was reduced in the apical region. The canalicular systems and osteocytes in the alveolar bone were abnormal, with reduced numbers of canaliculi and an altered osteocyte morphology. The loss of alveolar bone and cementum along with the detachment of the periodontal ligaments (PDL) led to the apical migration of the epithelial attachment and the formation of periodontal pockets.
Conclusion
Inactivation of DSPP leads to the loss of the alveolar bone and cementum and increased susceptibility to bacterial infections in the PDL of Dspp null mice. The fact that the loss of DSPP results in periodontal diseases indicates that this molecule plays a vital role in maintaining the health of the periodontium.
doi:10.1111/j.1600-0765.2012.01523.x
PMCID: PMC3514631  PMID: 22934831
25.  Simvastatin prevents alveolar bone loss in an experimental rat model of periodontitis after ovariectomy 
Background
Periodontitis is an inflammatory disease characterized by the loss of connective tissue and alveolar bone. There is an increasing evidence that periodontitis is associated with a number of chronic disease, including osteoporosis. Periodontitis and osteoporosis are both bone destructive diseases and of high prevalence in adult population. Osteoporosis could increase some inflammatory factors that also participate in the progression of periodontitis, so as to facilitate the alveolar bone resorption. Simvastatin, specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme reductase, is of pleiotropic effects including anti-catabolic and anabolic effect on bone metabolism. This study aimed to explore the local and systemic effect of simvastatin on maxillary in rats with both osteoporosis and periodontitis.
Methods
Thirty-six 4-month-old female Sprague Dawley rats were randomly assigned to six groups: sham group, ligature group, ovariectomized (OVX) + ligature group, local simvastatin administration to OVX + ligature rats (local simvastatin group), oral simvastatin administration to OVX + ligature rats (oral simvastatin group), local and oral simvastatin administration to OVX + ligature rats (L&O simvastatin group). One month after OVX, ligatures were placed on the maxillary first (M1) and second molars (M2) for 4 weeks on all rats except those in the sham group, followed by simvastatin treatment for 2 months. The maxillae, serum, and femurs were collected for further examination including micro-computed (micro-CT) tomography, hematoxylin and eosin (H&E) staining, tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assays (ELISA), and the three-point bending test.
Results
Local simvastatin administration increased alveolar crest height and prevented local alveolar bone loss without alteration of systemic bone loss. Oral administration prevented local and systemic bone loss with no effect on alveolar crest height.
Conclusions
Our results indicate that simvastatin has the potential of promoting bone formation and reducing alveolar bone loss in maxillary following ovariectomy (OVX) and ligature placement in rats.
doi:10.1186/s12967-014-0284-0
PMCID: PMC4192445  PMID: 25269614
Simvastatin; Alveolar bone loss; Periodontitis; Osteoporosis; Maxillary

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