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iNOS -derived Nitric Oxide Modulates Infection-stimulated Bone Loss
S.Y. Fukada1,
T.A. Silva2,
I.F. Saconato1,
G.P. Garlet3,
M.J. Ávila-Campos4,
J.S. Silva5 and
F.Q. Cunha1,*
1 Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, 14049-900, Ribeirão Preto SP, São Paulo, Brazil;
2 Department of Oral Surgery and Pathology, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;
3 Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil;
4 Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil; and
5 Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
Correspondence: * corresponding author, fdqcunha{at}fmrp.usp.br
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ABSTRACT
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Nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) plays an important role in host defense, as well as in inflammation-induced tissue lesions. Here we evaluated the role of NO in bone loss in bacterial infection-induced apical periodontitis by using iNOS-deficient mice (iNOS–/–). The iNOS–/– mice developed greater inflammatory cell recruitment and osteolytic lesions than WT mice. Moreover, tartrate-resistant acid-phosphatase-positive (TRAP+) osteoclasts were significantly more numerous in iNOS–/– mice. Furthermore, the increased bone resorption in iNOS–/– mice also correlated with the increased expression of receptor activator NF-kappaB (RANK), stromal-cell-derived factor-1 (SDF-1/CXCL12), and reduced expression of osteoprotegerin (OPG). These results show that NO deficiency was associated with an imbalance of bone-resorption-modulating factors, leading to severe infection-stimulated bone loss.
Key Words: Nitric oxide • osteoclastogenesis • RANK • RANKL • OPG • SDF-1/CXCL12
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INTRODUCTION
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Periapical lesions, resulting from dental pulp necrosis induced by bacterial infection, are characterized by the presence of migrated inflammatory cells. Together with resident connective tissue cells, the migrated cells release several mediators which contribute to curtail the progression of the infection, but which might also mediate the pathogenesis of surrounding tissue lesions and bone resorption (Nair, 1997).
Bone resorption is a consequence of an imbalance between osteoclast and osteoblast activity. Osteoclasts originate from hematopoietic precursors in bone marrow and emigrate from the peripheral circulation into bone to differentiate. One important key signal that orchestrates this mobilization is the chemokine stromal-cell-derived factor-1 (SDF-1 or CXCL12). SDF-1 binds only to its receptor CXCR4, which is widely expressed on leukocytes, mature dendritic cells, and osteoclast precursors, and which play an important role in the recruitment and migration of the murine osteoclast cell line (Wright et al., 2005).
The major regulatory mechanism of osteoclast activity is driven by the receptor activator of NF-kappaB (RANK), which belongs to the tumor necrosis factor (TNF) receptor superfamily. RANK, present on the surfaces of osteoclast precursors, is activated by RANK ligand (RANKL), a homotrimeric, TNF-like cytokine. This activation induces differentiation of osteoclasts, thus increasing bone breakdown. Conversely, osteoprotegerin (OPG), which is produced by periodontal ligament cells, fibroblasts, and osteoblasts, interrupts RANK activation by binding directly to RANKL (Boyle et al., 2003).
Nitric oxide (NO), a free radical, has been shown to have important effects on several inflammatory events, including the cell migration observed in periodontitis (Lappin et al., 2000) and radicular cysts (Takeichi et al., 1998). The role of this nitrogen-derived free radical in bone resorption is controversial. There are in vitro studies suggesting that NO inhibits bone resorption by inhibiting osteoclast formation and activity, stimulating apoptosis of osteoclast precursor cells, and enhancing osteoblast function (MacIntyre et al., 1991; van’t Hof and Ralston, 1997; Fan et al., 2004). Conversely, other reports have shown that NO may promote osteoclast maturation and enhance bone resorption induced by cytokines (Brandi et al., 1995; Ralston et al., 1995).
A recently published report showed that L-NAME treatment inhibited apical bone resorption, and that NO may promote apoptosis of osteoblasts (Lin et al., 2007). Taking into account the presence of iNOS in human periapical and periodontal disease, as well as the acknowledged role of NO in the modulation of inflammation and osteoclastogenesis, we undertook the present study to examine the role of iNOS-derived NO in determining the outcome of endodontic infection-induced bone loss, using an experimental model of periapical lesions.
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MATERIALS & METHODS
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Periapical Lesion Induction
Breeding pairs of mice with targeted deletion of the iNOS gene (iNOS–/–) (Laubach et al., 1995) and background wild-type (WT, C57BL/6) mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA). WT and iNOS–/– mice, from 6 to 8 wks of age, were anesthetized with 65 mg/kg ketamine and 7 mg/kg xylazine (i.p.). The pulp of the mandibular right first molars was exposed by means of a low-speed electric handpiece (Dabi Atlante, Ribeirão Pretol, Brazil) and a size  round bur. Exposed pulp was immediately inoculated with 10 µL of a mixture containing 106 of each of the following bacterial strains: Porphyromonas gingivalis (ATCC 33277), Prevotella nigrescens (ATCC 33563), Actinomyces viscosus (ATCC 91014), and Fusobacterium nucleatum (ATCC 10953). A bacterial mixture was prepared in methylcellulose (10% w/v).
The left first molars (without pulp exposure) were used as controls. All experiments were conducted in accordance with the ethical guidelines of the School of Medicine of Ribeirão Preto, University of São Paulo.
Specimen Preparation
After 21 days of pulp exposure, each hemi-mandible was fixed in fresh 10% neutral buffered formalin for 24 hrs and then decalcified in EDTA (4%). The specimens were embedded in paraffin and processed for light microscopic examination. Tissue blocks were cut in serial sections of 7 µm thickness.
Morphometric and TRAP Analyses
Serial sections chosen for the morphometric analysis of periapical lesions were stained with hematoxylin & eosin (n = 8 each group). The sections were photographed, and the lesion area was traced and measured with the software Image J 1.36 (National Institutes of Health, Bethesda, MD, USA). The lesion consisted of the inflammatory infiltrate areas delineated in the apical region and excluded intact tooth and bone structures. We also analyzed unexposed control teeth to determine the area of the periodontal ligament (mm2). The mean area was obtained by the analysis of 10–15 sections per tooth.
The sections from 6 animals in each group were stained with tartrate-resistant acid phosphatase (TRAP; Sigma-Aldrich, St. Louis, MO, USA). The number of TRAP+ osteoclasts on bone periphery adjacent to periapical lesions were counted and expressed as the number per millimeter of bone. The average of 6 mice from each group was statistically analyzed.
RNA Extraction and Real-time PCR
Periapical tissues surrounding root apices of the right and left sides (n = 6 each group) were extracted together with surrounding bone in a block specimen. The gingiva, oral mucosa, tooth crown, and bone marrow were dissected and discarded. Periapical tissues with surrounding bone were subjected to RNA extraction with TRIzol reagent (Invitrogen, Carlsbad, CA, USA). Complementary DNA (cDNA) was synthesized with 2 µg of RNA through a reverse-transcription reaction (Superscript II, Invitrogen). Real-time PCR analysis was performed in ABI Prism 7000 with the SYBR-green fluorescence quantification system (Applied Biosystems, Warrington, UK). Standard PCR conditions were 95°C (10 min), and then 40 cycles of 94°C (1 min), 58°C (1 min), and 72°C (2 min), followed by the standard denaturation curve. Primer sequences for mouse β-actin, iNOS, OPG, RANKL, RANK, and SDF-1/CXCL12 are described in the Table .
We used the mean Ct values from duplicate measurements to calculate expression of the target gene, with normalization to an internal control (β-actin), and relative to a calibrator "WT non-exposed", using the 2– DCt formula.
Statistical Analysis
We analyzed data with GraphPad Prism software, using the Mann-Whitney and two-way ANOVA tests to determine the level of significance between group means. Results are expressed as the mean ± SEM, and the experiments were repeated at least 3 times. For each test, a P < 0.05 was regarded as statistically significant.
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RESULTS
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iNOS Expression and Lesion Size in Periapical Lesion Sites
First, we examined the expression of iNOS mRNA in the periapical lesion site of wild-type mice 21 days after pulp exposure and bacterial inoculation, using real-time PCR. We observed that the level of iNOS mRNA was increased 3.6 times in periapical lesion sites when compared with the contralateral side (Fig. 1A). Bone resorption in the periapical region was measured by histomorphometry. We observed that the resorption was approximately 110% greater in iNOS–/– mice than in WT mice (Fig. 1B).
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Figure 1. Effect of pulp exposure followed by inoculation with 4 different oral pathogens in WT and iNOS–/– mice. Expression of iNOS mRNA levels ± SD in periapical region by real-time PCR (A). iNOS gene expression is normalized by β-actin expression. The experiment was repeated 3 times, and the difference between expression in non-exposed sites and that in exposed sites of WT mice was analyzed by the Mann-Whitney test, * p < 0.05 (n = 6 each group). Effects of pulp exposure and infection on bone resorption area in WT and iNOS–/– mice (B). Bars indicate means of lesion area ± SEM, n = 8 each group. Open columns indicated in the non-exposed tooth (contralateral side) in fact represent the area of normal periodontal ligament space; *p < 0.05 indicates difference between exposed and non-exposed sites; #p < 0.05 indicate difference between exposed WT and iNOS–/– mice analyzed by two-way ANOVA test. Visual examination showed no alteration in WT mice (C), but grossly evident orofacial abscess in 25% of iNOS–/– mice (D). Photomicrograph of periapical inflammatory lesions in WT (E,G) and iNOS–/– mice (F,H) 21 days after pulp exposure. Arrows indicate lesion area; H&E-stained sections. Original magnification is 10x and 40x, respectively.
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While no macroscopic alteration was noted in WT mice (Fig. 1C ), in 25% of the iNOS–/– mice, an abscess was seen to have formed, draining at the base of the jaw on the infected side (Fig. 1D). Microscopic analysis revealed total pulp necrosis and periapical lesion formation, characterized by intense inflammatory infiltration and apical bone loss in all teeth, with exposed and infected pulp, of both iNOS–/– and WT strains. However, the lesion size in iNOS–/– was greater (Figs. 1F, 1H) than that observed in WT mice (Figs. 1E, 1G).
Numbers of TRAP-positive Cells and the Expression of RANK and CXCL12 are Increased in iNOS–/– Mice
The determination of TRAP+ cell numbers per mm of bone in the periapical region showed a statistical difference between numbers of TRAP+ cells in non-exposed and exposed areas in WT (2.2 ± 0.5 and 5.4 ± 0.5 cells) and iNOS–/– mice (3.1 ± 0.7 and 8.2 ± 0.5 cells), and also between the exposed side in WT and iNOS–/– mice (Fig. 2).
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Figure 2. Photomicrograph of representative TRAP-positive stain and quantification of TRAP+ cells on bone surface. Photomicrographs show the TRAP-positive cells (arrows) in the apical region of WT (A) and iNOS–/– mice (B). TRAP-positive osteoclasts are shown by black arrows. b, bone; r, root; l, periodontal ligament. We assessed the osteoclasts on bone surfaces in the lesion areas of WT and iNOS–/– mice by counting the number of TRAP+ cells per mm of bone adjacent to periapical lesions (C). Descriptive analyses are expressed as mean ± SEM of n observations counted per mm of bone from 6 different mice in each group. *p < 0.05 indicates differences between exposed and non-exposed sites; #p < 0.05 indicates differences between exposed WT and iNOS–/– mice analyzed by two-way ANOVA test. Original magnification is 20x.
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Next, we evaluated whether there were changes in osteoclastic regulatory and chemotactic molecules. First, we observed that RANK, OPG, RANKL, and SDF-1/CXCL12 expression in apical tissue of exposed teeth was increased compared with that in the respective non-exposed areas of both strains. The increase in mRNA for RANK and CXCL12 in exposed teeth was greater in iNOS–/– than in WT mice (Figs. 3A, 3B). Conversely, the increase in OPG expression in exposed teeth was significantly lower in iNOS–/– compared with WT mice (Fig. 3C), and the expression of RANKL was similarly increased in exposed areas of WT and iNOS–/– mice (Fig. 3D).
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Figure 3. Expression of bone-resorptive regulatory mediators (A) RANK, (B) SDF-1/CXCL12, (C) OPG, and (D) RANKL levels ± SD in periapical lesions by real-time PCR. All gene expression data shown are relative to non-exposed WT mice. The experiment was repeated 3 times, and the differences in gene expressions were analyzed by two-way ANOVA test. *p < 0.05 indicates differences between exposed and non-exposed sites; #p < 0.05 indicates differences between exposed WT and iNOS–/– mice, n = 6 each group.
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DISCUSSION
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Pulp exposure followed by bacterial inoculation promotes reproducible apical chronic lesion formation in mice after 21 days (Chen et al., 1999). We used this well-established in vivo model to evaluate the role of NO in the pathogenesis of periapical disease in iNOS–/– mice. We observed that the genetic deletion of iNOS aggravated and increased the extension of apical lesions, including bone resorption.
Previous studies have shown an increase in iNOS expression a few hrs after induced pulpitis (Kawashima et al., 2005) and in human apical lesions (cysts and granulomas), suggesting a role for iNOS-derived NO in the regulation of pulpitis and periapical chronic inflammation (Takeichi et al., 1998). Other studies have shown that the plasma cells, macrophages, endothelial cells, and lymphocytes present in established apical lesions strongly reacted with iNOS antibody, while neutrophils within the abscess frequently showed relatively weak immunoreactivity to iNOS (Suzuki et al., 1999; Hama et al., 2007). Accordingly, the present study demonstrates increased iNOS gene expression in experimental bacteria-induced apical lesions in mice.
It is well-known that both macrophages and neutrophils exhibit microbicidal activity against aerobic and anaerobic bacteria by an iNOS-derived NO mechanism (Wei et al., 1995; Fierro et al., 1999; Gyurko et al., 2003). In an experimental model of periapical lesions similar to that used in the present study, it was observed that the reduction in mononuclear cell migration caused by MCP-1 (monocyte chemoattractant protein-1) deletion rendered the host more susceptible to infection (Chae et al., 2002). Further, it has been shown that infection-stimulated periapical bone destruction is correlated with decreased neutrophilic infiltration (Kawashima et al., 1999). This suggests that, in periapical infection, macrophages and neutrophils have a predominant role in bacterial clearance. Thus, in iNOS–/– mice, these cells present in the infection site should be less effective in controlling bacterial infection, leading to bacterial penetration into inflamed apical tissues, exacerbation of local inflammatory response, and, consequently, abscess formation. Furthermore, it is important to mention that in addition to increased bacterial infection, the deficiency of NO also contributes directly to increased leukocyte migration. In fact, there is evidence that NO down-modulates the leukocyte migration induced by different inflammatory stimuli (Hickey et al., 1997; Benjamim et al., 2002; Dal Secco et al., 2003).
In the iNOS–/– mice, we observed that significant alveolar bone loss around the infected root was associated with an augmentation of TRAP+ osteoclasts. Further, the iNOS–/– mice showed an up-regulation of SDF-1/CXCL12 mRNA when compared with WT mice, and the possible increase in this chemokine could imply an increase in the recruitment of osteoclast progenitor cells (Wright et al., 2005). In contrast to our data, it has been shown that osteoclast numbers and cathepsin K expression in the periodontium, in response to Porphyromonas gingivalis challenge, were decreased in iNOS–/– compared with WT mice (Gyurko et al., 2005). However, our results have shown that iNOS–/– mice had more pronounced periapical lesions, which correlated with an imbalance in bone-resorption-modulating factors. Accordingly, other authors have shown that iNOS deficiency or the pharmacological inhibition of NO can accelerate osteoclast formation and bone resorption in vivo and in vitro, decreases normal bone mass, exacerbates bone destruction in arthritis models, and interferes with normal fracture healing (Diwan et al., 2000; McCartney-Francis et al., 2001; Veihelmann et al., 2001). Differences in the models studied and in the mix of bacterial strains vs. pure Porphyromonas gingivalis may account for these discrepancies. Moreover, different tissues and/or stimuli could recruit different subsets of osteoclast precursors (Jacquin et al., 2006) that respond differently to iNOS-derived NO.
The extension of bone resorption is determined by diverse factors, including the number and activity rate of osteoclasts generated from their progenitor cells (Roux and Orcel, 2000; Wada et al., 2006). In this context, the differentiation and activation of osteoclasts observed in several inflammatory pathologies, such as rheumatoid arthritis and periodontitis, are determined by an imbalance in the expression of osteoclastogenic modulators, RANK and RANKL/OPG, and also of chemokine release (Haynes et al., 2001; Crotti et al., 2003; Vernal et al., 2006). The increased bone resorption in iNOS–/– mice correlated with the increased levels of RANK and SDF-1/CXCL12 and the reduced expression of OPG, which together converged positively for osteoclast formation. This could be a consequence of the more pronounced inflammation observed in this strain. However, the absence of NO may also contribute to the process, since there is evidence that NO led directly to decreased bone resorption. It has been shown that NO, produced endogenously or supplied by NO donors, exerts potent action by inhibiting the recruitment, proliferation, differentiation, activation, and/or survival of osteoclasts and their precursors (van’t Hof and Ralston, 2001; Fan et al., 2004). In agreement with our findings, previous studies have shown that NO inhibits bone resorption in vitro by increasing OPG production (Wang et al., 2004) and by inhibiting osteoclast formation (Fan et al., 2004).
In conclusion, this study points to an important role for iNOS-derived NO, controlling local infection and the progression of osteolytic lesions in a murine experimental model of apical periodontitis. The iNOS deficiency is associated with an imbalance in the bone-resorptive modulators RANK, SDF-1/CXCL12, and OPG. Furthermore, analysis of our data provides a new insight into the development of future therapeutic interventions with NO donors, which could prevent inflammatory bone loss.
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ACKNOWLEDGMENTS
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We are grateful to Giuliana Bertozi, Fabiola Mestriner, Ana Kátia dos Santos, Cristiane Milanezi, and Maria Riul for technical assistance. This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil.
Received for publication April 9, 2007.
Revision received August 5, 2008.
Accepted for publication September 2, 2008.
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References
|
|---|
- Benjamim CF, Silva JS, Fortes ZB, Oliveira MA, Ferreira SH, Cunha FQ (2002). Inhibition of leukocyte rolling by nitric oxide during sepsis leads to reduced migration of active microbicidal neutrophils. Infect Immun 70:3602–3610.[Abstract/Free Full Text]
- Boyle WJ, Simonet WS, Lacey DL (2003). Osteoclast differentiation and activation. Nature 423:337–342.[CrossRef][Medline]
[Order article via Infotrieve]
- Brandi ML, Hukkanen M, Umeda T, Moradi-Bidhendi N, Bianchi S, Gross SS, et al. (1995). Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms. Proc Natl Acad Sci USA 92:2954–2958.[Abstract/Free Full Text]
- Chae P, Im M, Gibson F, Jiang Y, Graves DT (2002). Mice lacking monocyte chemoattractant protein 1 have enhanced susceptibility to an interstitial polymicrobial infection due to impaired monocyte recruitment. Infect Immun 70:3164–3169.[Abstract/Free Full Text]
- Chen CP, Hertzberg M, Jiang Y, Graves DT (1999). Interleukin-1 and tumor necrosis factor receptor signaling is not required for bacteria-induced osteoclastogenesis and bone loss but is essential for protecting the host from a mixed anaerobic infection. Am J Pathol 155:2145–2152.[Medline]
[Order article via Infotrieve]
- Crotti T, Smith MD, Hirsch R, Soukoulis S, Weedon H, Capone M, et al. (2003). Receptor activator NF kappaB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis. J Periodontal Res 38:380–387.[Medline]
[Order article via Infotrieve]
- Dal Secco D, Paron JA, de Oliveira SH, Ferreira SH, Silva JS, Cunha FQ (2003). Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis. Nitric Oxide 9:153–164.[CrossRef][Medline]
[Order article via Infotrieve]
- Diwan AD, Wang MX, Jang D, Zhu W, Murrell GA (2000). Nitric oxide modulates fracture healing. J Bone Miner Res 15:342–351.[CrossRef][Medline]
[Order article via Infotrieve]
- Fan X, Roy E, Zhu L, Murphy TC, Ackert-Bicknell C, Hart CM, et al. (2004). Nitric oxide regulates receptor activator of nuclear factor-kappaB ligand and osteoprotegerin expression in bone marrow stromal cells. Endocrinology 145:751–759.[Abstract/Free Full Text]
- Fierro IM, Nascimento-DaSilva V, Arruda MA, Freitas MS, Plotkowski MC, Cunha FQ, et al. (1999). Induction of NOS in rat blood PMN in vivo and in vitro: modulation by tyrosine kinase and involvement in bactericidal activity. J Leukoc Biol 65:508–514.[Abstract]
- Gyurko R, Boustany G, Huang PL, Kantarci A, Van Dyke TE, Genco CA, et al. (2003). Mice lacking inducible nitric oxide synthase demonstrate impaired killing of Porphyromonas gingivalis. Infect Immun 71:4917–4924.[Abstract/Free Full Text]
- Gyurko R, Shoji H, Battaglino RA, Boustany G, Gibson FC 3rd, Genco CA, et al. (2005). Inducible nitric oxide synthase mediates bone development and P. gingivalis-induced alveolar bone loss. Bone 36:472–479.
- Hama S, Takeichi O, Saito I, Ito K (2007). Involvement of inducible nitric oxide synthase and receptor for advanced glycation end products in periapical granulomas. J Endod 33:137–141.[Medline]
[Order article via Infotrieve]
- Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM (2001). Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology (Oxford) 40:623–630.[Abstract/Free Full Text]
- Hickey MJ, Sharkey KA, Sihota EG, Reinhardt PH, Macmicking JD, Nathan C, et al. (1997). Inducible nitric oxide synthase-deficient mice have enhanced leukocyte-endothelium interactions in endotoxemia. FASEB J 11:955–964.[Abstract]
- Jacquin C, Gran DE, Lee SK, Lorenzo JA, Aguila HL (2006). Identification of multiple osteoclast precursor populations in murine bone marrow. J Bone Miner Res 21:67–77.[CrossRef][Medline]
[Order article via Infotrieve]
- Kawashima N, Niederman R, Hynes RO, Ullmann-Cullere M, Stashenko P (1999). Infection-stimulated infraosseus [sic] inflammation and bone destruction is [sic] increased in P-/E-selectin knockout mice. Immunology 97:117–123.[CrossRef][Medline]
[Order article via Infotrieve]
- Kawashima N, Nakano-Kawanishi H, Suzuki N, Takagi M, Suda H (2005). Effect of NOS inhibitor on cytokine and COX2 expression in rat pulpitis. J Dent Res 84:762–767.
- Lappin DF, Kjeldsen M, Sander L, Kinane DF (2000). Inducible nitric oxide synthase expression in periodontitis. J Periodontal Res 35:369–373.[CrossRef][Medline]
[Order article via Infotrieve]
- Laubach VE, Shesely EG, Smithies O, Sherman PA (1995). Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci USA 92:10688–10692.[Abstract/Free Full Text]
- Lin SK, Kok SH, Lin LD, Wang CC, Kuo MY, Lin CT, et al. (2007). Nitric oxide promotes the progression of periapical lesion via inducing macrophage and osteoblast apoptosis. Oral Microbiol Immunol 22:24–29.[Medline]
[Order article via Infotrieve]
- MacIntyre I, Zaidi M, Alam AS, Datta HK, Moonga BS, Lidbury PS, et al. (1991). Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. Proc Natl Acad Sci USA 88:2936–2940.[Abstract/Free Full Text]
- McCartney-Francis NL, Song X, Mizel DE, Wahl SM (2001). Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease. J Immunol 166:2734–2740.[Abstract/Free Full Text]
- Nair PN (1997). Apical periodontitis: a dynamic encounter between root canal infection and host response. Periodontol 2000 13:121–148.
- Ralston SH, Ho LP, Helfrich MH, Grabowski PS, Johnston PW, Benjamin N (1995). Nitric oxide: a cytokine-induced regulator of bone resorption. J Bone Miner Res 10:1040–1049.[Medline]
[Order article via Infotrieve]
- Roux S, Orcel P (2000). Bone loss. Factors that regulate osteoclast differentiation: an update. Arthritis Res 2:451–456.[CrossRef][Medline]
[Order article via Infotrieve]
- Suzuki N, Okiji T, Suda H (1999). Enhanced expression of activation-associated molecules on macrophages of heterogeneous populations in expanding periapical lesions in rat molars. Arch Oral Biol 44:67–79.[CrossRef][Medline]
[Order article via Infotrieve]
- Takeichi O, Saito I, Hayashi M, Tsurumachi T, Saito T (1998). Production of human-inducible nitric oxide synthase in radicular cysts. J Endod 24:157–160.[Medline]
[Order article via Infotrieve]
- van’t Hof RJ, Ralston SH (1997). Cytokine-induced nitric oxide inhibits bone resorption by inducing apoptosis of osteoclast progenitors and suppressing osteoclast activity. J Bone Miner Res 12:1797–1804.[CrossRef][Medline]
[Order article via Infotrieve]
- van’t Hof RJ, Ralston SH (2001). Nitric oxide and bone. Immunology 103:255–261.[CrossRef][Medline]
[Order article via Infotrieve]
- Veihelmann A, Landes J, Hofbauer A, Dorger M, Refior HJ, Messmer K, et al. (2001). Exacerbation of antigen-induced arthritis in inducible nitric oxide synthase-deficient mice. Arthritis Rheum 44:1420–1427.[CrossRef][Medline]
[Order article via Infotrieve]
- Vernal R, Dezerega A, Dutzan N, Chaparro A, Leon R, Chandia S, et al. (2006). RANKL in human periapical granuloma: possible involvement in periapical bone destruction. Oral Dis 12:283–289.[Medline]
[Order article via Infotrieve]
- Wada T, Nakashima T, Hiroshi N, Penninger JM (2006). RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12:17–25.[CrossRef][Medline]
[Order article via Infotrieve]
- Wang FS, Wang CJ, Chen YJ, Huang YT, Huang HC, Chang PR, et al. (2004). Nitric oxide donor increases osteoprotegerin production and osteoclastogenesis inhibitory activity in bone marrow stromal cells from ovariectomized rats. Endocrinology 145:2148–2156.[Abstract/Free Full Text]
- Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP, et al. (1995). Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375:408–411.[CrossRef][Medline]
[Order article via Infotrieve]
- Wright LM, Maloney W, Yu X, Kindle L, Collin-Osdoby P, Osdoby P (2005). Stromal cell-derived factor-1 binding to its chemokine receptor CXCR4 on precursor cells promotes the chemotactic recruitment, development and survival of human osteoclasts. Bone 36:840–853.[CrossRef][Medline]
[Order article via Infotrieve]
Journal of Dental Research, Vol. 87, No. 12,
1155-1159 (2008)
DOI: 10.1177/154405910808701207
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ABSTRACT
INTRODUCTION