Clinical and Experimental Hypertension, 2013; 35(1): 1–5Copyright © Informa Healthcare USA, Inc.ISSN 1064-1963 print/1525-6006 onlineDOI: 10.3109/10641963.2012.683969

Arterial Hypertension Perpetuates Alveolar Bone Loss

Janine Montenegro Toscano Moura de Medeiros Vanderlei,1 Michel Reis Messora,1 PatríciaGarani Fernandes,1 Arthur B. Novaes Jr.,1 Daniela Bazan Palioto,1 Marcio Fernando de MoraesGrisi,1 Sergio Luis Scombatti de Souza,1 Raquel Fernanda Gerlach,2 Cristina Antoniali,3

Mario Taba Jr.1

1Department of Oral Surgery and Periodontology, Ribeirão Preto School of Dentistry, University of São Paulo, São Paulo,Brazil, 2Department of Morphology, Estomatology and Physiology, Ribeirão Preto School of Dentistry, University of São Paulo,São Paulo, Brazil, 3Department of Basic Sciences, School of Dentistry of Araçatuba, UNESP –Universidade Estadual Paulista,Araçatuba, São Paulo, Brazil

Abstract

Few studies have focused on the impact of hypertension on the progression of periodontitis (PD). The purpose of thisstudy was to evaluate whether hypertension affects PD by enhancing bone loss even after the stimulus for PD induction isremoved. Ligature-induced PD was created on the first mandibular molars of spontaneously hypertensive rats (SHR) andnormotensive rats (Wistar Kyoto—WKY). The animals were assigned to non-ligated controls (C) and PD groups: WKY-C,WKY-PD, SHR-C, and SHR-PD. After 10 days, five animals of each group were killed and the ligatures of the other animalswere removed. On the 21st day (11 days without PD induced), the remaining animals were killed. The jaws were defleshedand the amount of bone loss was measured. After 10 days, the PD groups showed more bone loss than its controls (P <.05); SHR-PD¼ 0.72� 0.05 mm, SHR-C¼ 0.39� 0.04 mm,WKY-PD¼ 0.75� 0.04 mm, andWKY-C¼ 0.56� 0.04 mm.The cumulative bone loss on day 21 (0.94 � 0.13 mm) was significantly worse than on day 10 only in SHR-PD group (P <.05). The final bone loss differences between PD and C groups accounted for 102% (SHR) and 26% (WKY) increase incomparison with the initial control levels. Hypertension is associated with progressive alveolar bone loss even when thestimulus for PD induction is removed and it may be speculated that host condition perpetuates alveolar bone loss.

Keywords: periodontitis, hypertension, alveolar bone loss, SHR, animal model

INTRODUCTION

Periodontitis (PD) is an inflammatory disease that affectsthe supporting bone around the teeth, leading to tooth loss(1). It is very prevalent, afflicting over 50% of the adultpopulation in the United States, and approximately 10%have severe disease concomitant with early tooth loss (2).Although the initiation of PD is dependent on bacterialchallenge, the host response to bacterial attack is critical (1).

Experimental and epidemiological studies have showna correlation between hypertension and teeth survival,which is related to the potential harm of systemic inflam-mation on the bone density and quality (3–7).

Hypertension is a very prevalent andmultifactorial con-dition characterized by increased peripheral vascular resis-tance due to a vascular remodeling (8,9). The systemicinflammatory process due to endothelial dysfunction,which is the initial step in the development of hypertensionand atherosclerosis, may also be the cause of alterations inthe periodontium. Endothelial dysfunction disturbs the

regulatory balance by a decrease in nitric oxide (10) andan increase in interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), andC-reactive protein (CRP) blood levels (5).In addition,moderate to severe PDalso increases systemiclevels of inflammatory biomarkers such as CRP, IL-6, andTNF-α (11,12).

Besides the systemic inflammation, hypertension alsoaffects the calcium metabolism by activating parathyroidhormone, in turn causing osteoclast differentiation andincreased mobilization of calcium from bone (6,9). Thisphenomenon decreases bone mineral density and preju-dices bone repair in both humans and spontaneouslyhypertensive rats (SHR) (7,9,13).

Despite the evidences, few studies have focused on theimpact of the hypertensive status on the periodontal tis-sues (6,14). In view of the hypertension prevalence and theimportance of periodontium in health quality, the purposeof this study was to evaluate, morphometrically, whetherhypertensive condition affects bonemetabolism by enhan-cing bone loss in experimental PD.

Address correspondence to Mario Taba Jr., DDS, MSc, PhD, Department of Oral Surgery and Periodontology, Ribeirão Preto School ofDentistry, University of São Paulo, Avenida do Café – s/n, 14040-904 Ribeirão Preto, São Paulo, Brazil. E-mail: mtaba@usp.br

Received 28 February 2012; revised 3 April 2012; accepted 4 April 2012.

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METHODS

AnimalsThe research protocol was previously approved by theInstitutional Committee for Animal Care and Use ofUniversity of São Paulo, Ribeirão Preto, Brazil. Theanimals were housed in groups of five rats per cage, inroom with 12-hour light/dark cycle, and temperaturebetween 22�C and 24�C and had free access to standardrat chow and drinking water ad libitum. Forty male ratswere used in this study. Spontaneously hypertensiverats and normotensive male rats (Wistar Kyoto—WKY) were assigned to non-ligated control (C) andPD groups as follows: WKY-C, WKY-PD, SHR-C,and SHR-PD.

Experimental Design and Induction of PDThe animals of PD groups were submitted to generalanesthesia by intraperitoneal administration of xylazine(8 mg/kg) and ketamine (75 mg/kg) to receive cottonligatures on the first mandibular molars. This experi-mental PD model is widely used and has been shown tofacilitate bacteria-induced inflammation and periodontaltissue breakdown (15).

After 10 days, five animals of each group (WKY-C,WKY-PD, SHR-C, and SHR-PD) were killed to evalu-ate induced bone loss, and the ligatures of the otheranimals of PD groups were removed. On the 21st day,11 days without ligatures, the remaining animals werekilled to have the non-induced bone level changes mea-sured. This experimental design was based on previousstudies (15,16).

Body weight and blood pressure were measuredweekly. The systolic blood pressure (SBP) was assessedby tail-cuff plethysmography, and rats were considered tobe hypertensive when SBP was higher than 150 mm Hg.

Measurement of Alveolar Bone LevelAfter the rats were killed, the rat jaws were excised,biologically and chemically defleshed, and stained with1% aqueous methylene blue in order to differentiatebone from teeth and enhance the visibility of the cemen-toenamel junction (CEJ).

Using a stereomicroscope (Leica MZ6, LeicaMicrosystems GmbH, Wetzlar, Germany) with a colorvideo camera mounted on it and coupled to a computer,the lingual surfaces of the defleshed jaws were recordedin a standardized manner (20� magnification).

The distance between the alveolar bone crest (ABC)and the CEJ (ABC–CEJ, mm) was measured in the distalroot surface of the first molar, mesial root surface of thesecond molar, and in the central point of the interprox-imal area between first and second molars (Figure 1),respectively, using an image analysis software (Image J—National Institutes of Health, Washington, DC, USA).In order to avoid error, the average of the three measureswas used for analysis.

Statistical AnalysisAll data are expressed as mean � SEM. For statisticalanalysis, the mean of the three ABC–CEJ distances mea-sured in each sample was used. Differences among thegroups were analyzed by two-way analysis of variance(two-way ANOVA) followed by Duncan’s test for multi-ple comparisons and values of P< .05 were considered assignificant.

RESULTS

The effects of hypertension on PD were monitored bymeasuring the bone loss using a ligature-induced PDmodel and also by evaluating the alveolar bone lossafter ligature removal in hypertensive rats. During theexperiment, no significant body weight changes wereobserved in the groups. However, the average bodyweight was different between groups, 247.1 � 5.3 g forthe SHR group and 334.5� 8.1 g for theWKY group. Asexpected, all animals in the SHR group presented ele-vated blood pressure. The mean level of the SBP for theSHR group was 192.7 � 1.1 mm Hg and for the WKYgroup was 120.7 � 1.6 mm Hg.

Measurement of Alveolar Bone LevelTo evaluate the impact of hypertension on bone altera-tions in progressive PD, the distance between the ABCand the CEJ (ABC–CEJ, mm) was measured at threepoints in the interproximal area between first and secondmolars in hypertensive rats (SHR) (Figure 1). For com-parison reasons, WKY rats were used as a normotensivecontrol, as described in the section “Methods”.

After 10 days of ligature-induced PD, PD groupsshowed more bone loss than controls (P < .05) (SHR-PD ¼ 0.72 � 0.05 mm, SHR-C ¼ 0.39 � 0.04 mm,WKY-PD ¼ 0.75 � 0.04 mm, and WKY-C ¼ 0.56 �0.04 mm). There was no difference (P > .05) betweenSHR-PD and WKY-PD groups (Figure 2).

After 21 days, PD groups showed superior cumulativebone loss than the control groups (P < .05); however, nodifference was observed between SHR-PD and WKY-PD groups (P > .05). The distances ABC–CEJ in eachgroup were SHR-PD¼ 0.95� 0.13 mm, SHR-C¼ 0.47� 0.04 mm, WKY-PD ¼ 0.88 � 0.04 mm, and WKY-C¼ 0.70 � 0.04 mm (P < .05), respectively (Figure 2).After removal of the stimulus for bone resorption, anadditional bone loss was observed only in SHR-PDgroup (P < .05) (Figure 2).

To evaluate the disease progression after ligatureremoval, an additional bone loss was observed by calculat-ing the difference of distance ABC–CEJ (mm) between 10and 21 days. The values were SHR-PD¼ 0.23mm, SHR-C ¼ 0.08 mm, WKY-PD ¼ 0.13 mm, and WKY-C ¼0.13mm. Figure 3 shows that the percentage of additionalbone loss observed between 10 and 21 days in WKY-PDgroup (17%) was similar to its respective control WKY-C(23%), while SHR-PD (32%) exhibited more additionalbone loss than SHR-C (19%).

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The percentage of bone loss in SHR was superior toWKY between PD and control groups, mainly on the21st day (102% and 26%, respectively) (Figure 4).

DISCUSSION

Few studies have focused on the impact of the hyperten-sive status on the periodontal tissues and evaluated theeffect of hypertension on the alveolar bone in the presenceof infectious challenge such as PD (6,14). However, those

studies (6,14) only evaluated the effects of hypertensionon periodontal tissues with ligature presence and did notassess these effects after ligature removal. More impor-tant, the ligature removal and consequent elimination ofthe stimulus for bone loss would allow us to observe therole of host response in PD progression. Moreover, webelieve this is the first investigation on the impact of hostresponse on the severity of PD progression even afterligature removal in hypertensive rats.

In order to measure the effects of the hypertensivecondition on alveolar bone, the SHR was chosen as theexperimental animal model. The spontaneously hyper-tensive rats have shown systemic manifestations similarto the human disorder (17). These animals presenthemodynamic, endocrine, and end-organmanifestationsthat may enhance bone loss and impair bone repair (9).

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Figure 2. Bone levels for SHR and WKY groups. The measure-ments indicate the average ABC–CEJ (mm) distance of SHR andWKY between 10 and 21 days after ligature placement. The mea-sures on the 21st day correspond to the effects of 10 days of ligaturePD-induced period and the additional 11 days without ligature.The intragroup analysis shows a superior bone loss in PD groupscompared with control groups. The analysis of PD progressionafter ligature removal which occurred between 10 and 21 daysrevealed a bone loss progression only in SHR-PD (P < .05). Thebars represent the mean � SEM of ABC–CEJ (mm) in the inter-proximal area between first and second molars. *P < .05 wasconsidered as statistically significant (two-way ANOVA andDuncan’s test). Abbreviations: ABC–CEJ – alveolar bone crest–cementoenamel junction; PD – periodontitis; SHR – sponta-neously hypertensive rats; WKY – Wistar Kyoto—normotensivecontrol.

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Figure 3. Percentage of progressive bone loss after ligature removal.The graph illustrates the contribution of each group to the totalamount of additional bone loss after ligature removal. The addi-tional bone loss percentage was calculated by the difference ofmeans of ABC–CEJ (mm) between 10 and 21 days. The percentageof additional bone loss in WKY-PD group (17%) was similar tothat presented by WKY-C (23%), while SHR-PD (32%) exhibiteda superior additional bone loss than SHR-C (19%). Abbreviations:ABC–CEJ – alveolar bone crest–cementoenamel junction; SHR –

spontaneously hypertensive rats; WKY – Wistar Kyoto—normo-tensive control; PD – periodontitis group; C – control group.

Figure 1. Photographs of the defleshed jaw after methylene blue staining. Illustrative measurement of bone loss of control (A) and PD groups(B)—20� magnification. Appreciate the amount of bone loss in the PD group (B) consisting of apical migration of the bone crest andexposure of interdental and furcation areas. The distance between ABC and CEJ was measured at three points in the interproximal areabetween first and second molars (vertical lines). The mean � SEM of the three measures was calculated for the statistical analysis.Abbreviations: ABC – alveolar bone crest; CEJ – cementoenamel junction; PD – periodontitis.

© 2013 Informa Healthcare USA, Inc.

Hypertension Perpetuates Bone Loss 3

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The Wistar Kyoto strain was used as a normotensivecontrol. Because SHR and WKY have the same geneticbackground except hypertension, the WKY strain hasbeen used in most of studies and accepted as the mostappropriate normotensive control for SHR (18,19).

In this study, the SHR group showed a very consistenthigh blood pressure level throughout the study, indicatingthat the hypertensive condition was negatively affectingboth ligature and no-ligature phases of the study. In thesame way, there were no significant weight changes thatcould directly or indirectly cause relevant nutritional defi-ciencies to be associated with progressive bone loss.

Although animals’ body weight had not changed dur-ing the study, it was observed that SHR were smaller andlighter than WKY. For this reason, in this study, dataconcerning bone loss severity (Figure 4), as well as dataconcerning additional bone loss after ligature removal(Figure 3) were presented in percentage, in order tominimize variations in sizes between groups.

In the intragroup analysis, the PD groups showedsuperior bone loss after 10 days of ligature placementcompared with control groups (Figure 2), indicatingthat the ligature method was efficient at inducing PD(20). This result is in accordance with Bastos et al. (6),who verified more bone loss in the furcation area andLeite et al. (14), who observed collagen degradation onlyin the ligated sites; in both studies SHR model was used.

No significant difference in ABC–CEJ distance wasobserved between SHR-PD and WKY-PD groups; thisobservation is in accordance with Bastos et al. (6).However, in this study, it can be observed that ABC–

CEJ values in WKY-C group were higher than thoseobserved in SHR-C group. Most of the differencesbetween SHR-C and WKY-C groups can be explained

due to the body size disparity between WKY and SHRanimals.

Although the WKY demonstrated higher values ofABC–CEJ in comparison with SHR, it was possible toobserve that the progressive bone loss was more evidentin the SHR group on day 10 and mainly on day 21(Figure 4).

On day 21, 11 days without ligatures, PD groupsshowed accumulated bone loss superior to controlgroups, indicating that neither SHR norWKY presentedbone formation at non-ligature phase (without stimulusfor bone loss) of the study. However, Figure 2 shows ahigher bone loss between 10 and 21 days only in SHR-PD group. These results indicate that bone loss afterligature removal was more severe when the hypertensivecondition was present. This result is in accordance withBastos et al. (6), which concluded that SHR presentedsevere alterations in alveolar bone independently ofinflammation. Additionally, it has been demonstratedthat SHR presented lower bone density (6,9,21–23)and impaired bone healing in tibial defects comparedwith normotensive rats (9).

Our study showed that the percentage of additionalbone loss after ligature removal in WKY-PD group wassimilar to the one presented by WKY-C, while SHR-PDexhibited a superior additional bone loss than its controlgroup (Figure 3). In addition to the severe bone loss inSHR-PD group, on day 10 and mainly after ligatureremoval, the pattern of PD progression occurred in aninverse way in SHR and WKY groups. After ligatureremoval, WKY demonstrated a diminished trend ofbone loss in contrast to SHR that exhibited a progressivepattern of bone loss (Figure 4). AlthoughWKY and SHRanimals had opposed results in our study, the compar-ison of this result with other strains is critical since theymight present different patterns of bone loss (24) andbone healing after the ligature removal (25).

The results of this study revealed that SHR animalspresented more severe bone loss than WKY, as shown inFigure 4. In addition, these SHR animals had the alveolarbone loss perpetuated, even after ligature removal (i.e.,removal of the stimulus for bone loss) in contrast to thenormotensive group, which had a lower pattern of boneloss on day 21, suggesting an important role of the hostresponse in PD progression (Figure 4). Possible explana-tions for these observations can be linked to both organicchanges in hypertensive organisms: (i) changes in bonemetabolism and (ii) systemic inflammatory process. Inthis regard, besides hypertension per se, other systemicfactors may have contributed to the observed results. Forexample, oxidative stress and systemic inflammation pre-sented in hypertensive organisms are known factors thatcan affect the periodontal status (10,12,26,27). Therefore,further investigation on monitoring the markers of sys-temic inflammation and oxidative stress associated withthe usage of host modulating agents, which decreaseblood pressure and inflammation is necessary to confirmthe effect of hypertension on the periodontal status.

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Figure 4. Severity of alveolar bone loss (%). Percentage differenceof bone loss between PD and control groups (between 10 and 21days). The spontaneously hypertensive rats group presented moresevere bone loss compared with WKY groups mainly on the 21stday, 11 days after ligature removal. After ligature removal, WKYshowed a diminished trend of bone loss, while SHR exhibited aprogressive pattern of bone loss. Abbreviations: SHR – sponta-neously hypertensive rats; WKY – Wistar Kyoto—normotensivecontrol.

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Based on the results, we observed two important char-acteristics related to PD in the SHR group: (i) theamount of induced bone loss was higher during the first10 days of the PD-induced phase with a (ii) progressivepattern of bone loss after stimulus removal fromday 11 today 21. Therefore, it may be speculated the hypertensionper se or together with systemic disorders presented inhypertensive organisms is associated with severe boneloss and perpetuates the tissue degradation even afterremoval of the stimulus for bone resorption.

Although this experimental design is limited, it sup-ports the proposal that systemic conditions where inflam-mation plays an important role alter periodontal diseasesusceptibility and may require additional care and hostmodulatory therapies.

ACKNOWLEDGMENTS

The authors thank Raquel Carros Antonio, AdrianaL. Almeida, Kléber Tanaka Suzuki, and Ana CarolinaO. Souza from Ribeirão Preto School of Dentistry; LuizFernando Ferreira from UNILAVRAS; and AdrianaM. M. Silveira e Souza from Ribeirão Preto MedicineSchool for their invaluable contributions to this study.

Declaration of interest: This study was supported byState of São Paulo Research Foundation FAPESP, Brazil(no. 2007/07007-2). The authors report no conflicts ofinterest. The authors alone are responsible for the con-tent and writing of the paper.

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