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J Dent Res 82(10): 791-795, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Parathyroid Hormone Protects against Periodontitis-associated Bone Loss

S.P. Barros1,*, M.A.D. Silva1, M.J. Somerman2,3, and F.H. Nociti, Jr.2,4

1 Department of Morphology, Division of Histology, School of Dentistry at Piracicaba, University of Campinas, Av. Limeria, 901, 13414-903 Piracicaba SP, Brazil;
2 Department of Periodontics, School of Dentistry, University of Washington, Seattle;
3 Department of Periodontics/Prevention/Geriatrics, School of Dentistry, University of Michigan, Ann Arbor; and
4 Department of Prosthodontics/Periodontics, Division of Periodontics, School of Dentistry at Piracicaba, University of Campinas, Brazil;

*corresponding author, sbarros{at}fop.unicamp.br


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Parathyroid hormone (PTH) functions as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. In addition to the well-established catabolic effects (activation of bone resorption) of PTH, it is now recognized that intermittent PTH administration has anabolic effects (promotion of bone formation). The aim of this study was to investigate whether intermittent administration of PTH in rodents would block the alveolar bone loss observed in rats when a ligature model of periodontitis is used. Morphometric analysis showed that intermittent PTH administration (40 µg/kg) was able to protect the tooth site from periodontitis-induced bone resorption. In addition, there was a significant reduction in the number of inflammatory cells at the marginal gingival area in sections obtained from animals receiving PTH compared with control animals. These findings demonstrated that intermittent PTH administration was able to protect against periodontitis-associated bone loss in a rodent model.

KEY WORDS: parathyroid hormone • periodontitis • anabolism


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Parathyroid hormone (PTH) functions as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis, producing several distinct and independent effects on the bone remodeling process, resulting in both bone formation (anabolic activity) and bone resorption (catabolic activity), e.g., continuous infusion of PTH decreases bone mass by stimulating osteoclast activity, while intermittent administration increases bone mass by stimulating osteoblast differentiation (Neer et al., 2001). The impressive and relevant results obtained in clinical trials (Neer et al., 2001; Horwitz et al., 2003) resulted in approval by the US Food & Drug Administration (FDA) for FORTEO® (PTH) to treat osteoporosis.

Various actions of PTH on cells of the osteoblast lineage affect the process of remodeling. PTH modulates cell morphology, proliferation, and matrix gene/protein expression (Canalis et al., 1989). These effects of PTH on bone metabolism are mediated by its binding to G-protein-coupled receptors (GPCR) on stromal and osteoblastic cells (Swarthout et al., 2001). GPCR stimulation of osteoblast-mediated bone formation is typically followed by osteoclast-mediated bone resorption, and different signaling pathways are thought to be involved in mediating these two actions. It has been suggested that the kinetics of GPCR activation/deactivation may determine whether GPCR stimulation is anabolic or catabolic. Two key factors secreted by osteoblasts, T-lymphocytes, and stromal cells—osteoprotegerin (OPG) and receptor activator of NF{kappa}ß ligand (RANKL)—have been linked to anabolic and catabolic activity, respectively (Simonet et al., 1997). Notably, PTH has been shown to regulate OPG and RANKL expressions.

Osteoclast activation requires induction of RANKL, a member of the tumor necrosis factor (TNF) ligand family—also called ODF/ TRANCE/OPGL—that stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF). Osteoclast precursors that express RANK (receptor activator of NF{kappa}ß) recognize RANKL expressed by osteoblasts and differentiate into osteoclasts in the presence of M-CSF (Martin and Ng, 1994). In contrast, OPG acts as a decoy and blocks RANKL-mediated activation of osteoclast activity.

Lipopolysaccharides (LPS)/endotoxin, biologically active pro-inflammatory factors found in the cell walls of Gram-negative bacteria, have been identified as factors involved in stimulating bone resorption. Analysis of current data indicates that prolonged or excessive production of such pro-inflammatory factors represents an important etiologic factor in bone loss associated with chronic inflammatory diseases, such as periodontitis.

Therefore, the aim of the present study was to determine whether or not intermittent administration of PTH (1-34), in rats subjected to periodontal disease, would result in protection against periodontitis-associated bone loss. As described here, PTH administration proved to protect animals from periodontitis-associated bone loss when compared with placebo-treated animals.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
Twenty male Wistar rats, aged 4 wks at the beginning of this study, were housed in the animal research facility at the University of Campinas. They were maintained in plastic cages and fed ad libitum with standard rat diet. The experimental procedures were approved by the Institutional Animal Research Committee at the University of Campinas (São Paulo, Brazil).

Experimental Design
The animals were treated under general anesthesia obtained by intramuscular administration of ketamine (1.0 mL/kg). To induce periodontitis, we randomly assigned a mandibular first molar in each animal to receive cotton ligature (CorrenteTM #10, São Paulo, SP, Brazil), placed submarginally. Contralateral teeth were left unligated to serve as controls. Animals were randomly assigned to one of two treatments (10 animals/group). Therefore, this resulted in four sub-groups for analysis: (1) PTH-treated ligated, (2) PTH-treated unligated, (3) placebo (vehicle) ligated, and (4) placebo unligated. The treated group received 40 µg/kg of PTH (1-34) prepared in 1% acetic acid, injected subcutaneously, 3 times a week for 4 wks, and the placebo group received the same volume of vehicle (1% acetic acid in water), under the identical protocol. The intermittent PTH schedule and dose used in the present study were based on previous studies by Iida-Klein et al.(2002) and Hagino et al.(2001). After 30 days (24 hrs after the last injection), the animals were killed. The jaws were removed and fixed in 4% neutral formalin for 48 hrs. The specimens were demineralized in a 5% EDTA/phosphate-buffered saline solution for around 72 days. Paraffin serial sections (7 µm), prepared in a mesio-distal direction, were obtained and stained with hematoxylin and eosin.

Histomorphometric Analysis
Using an image analysis system (Image-Pro®; Media Cybernetics, Silver Spring, MD, USA) and 5 sections per specimen, we histometrically determined the area between the bone crest and cementum surface in the furcation regions of ligated and unligated teeth. The sections were blindly presented for measurements by one examiner (MADS), and the data were then averaged to allow for intra- and intergroup analysis.

Quantification of Inflammatory Cells
We calculated the number of inflammatory cells (mono- and polymorphonuclear leukocytes) using the Zeiss Vision Image Analysis Program KS 400 (Kontron Elektron GmbH, Eching, Germany), at 400X magnification, by counting the number of inflammatory cells among the total number of cells present in the gingival area, where 12 fields were randomly chosen.

Statistical Analysis
Data were expressed as mean and standard deviation (mm2), and statistical differences in bone loss area and in inflammatory cell number were subjected to one-way analysis of variance (ANOVA) and Tukey’s Multiple Comparison Test at a 5% level of significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Histological analysis of sections obtained from ligated teeth, placebo group (Fig. 1AGo), indicated significant bone loss in the molar teeth furcation area when compared with the contralateral unligated teeth from PTH- or placebo-treated animals (Fig. 1BGo) or with ligated teeth from the PTH-treated group (Fig. 1CGo). Such findings were noted in all 10 samples. In marked contrast, the ligated molars in the animals that received intermittent PTH (40 µg/kg) showed no bone loss within the furcation area in comparison with placebo-treated ligated teeth (Fig. 1BvsGo . 1A), a finding observed in sections from all 10 molars. Statistical analysis showed no significant difference in histomorphometric measurements in sections obtained from ligated teeth, PTH-treated animals, compared with unligated molars from either the placebo- or PTH-treated groups (Fig. 1DGo). In the furcation area from placebo-treated ligated teeth, multinucleated osteoclasts were observed (Figs. 2A, 2BGoGo), and the periodontal ligament fibers were disarranged (Fig. 2CGo). These findings were not seen in tissues from ligated and unligated PTH-treated animals or from the placebo-treated unligated group.




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  		Figure 1. Histological aspect of molar furcation area for the different experimental groups. (A) Ligated tooth from the placebo group. The extension of the PL area indicates bone loss due to induction of periodontitis. (B) Unligated tooth from the placebo group. (C) Ligated tooth from a PTH-treated animal. Dentin (D), periodontal ligament area (PL), alveolar bone (B). Scale bar represents 0.25 mm. (D) Mean ± standard deviation of the area between bone crest and cementum surface (mm2) in the furcation area of ligated teeth from PTH-treated animals in comparison with the ligated and unligated teeth from the placebo group (*p < 0.05). Note: Similar findings were observed in sections obtained from unligated teeth regardless of treatment (PTH vs. placebo). N = 10/group.

 


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  		Figure 2. Histological aspects of the furcation area. (A) Low magnification of a ligated molar from the placebo-treated group. (B) Higher magnification: Osteoclasts and resorption pits can be observed (OC/arrows) in the bone area. (C) Periodontal ligament region: Disarrangement of periodontal ligament fibers can be observed. Periodontal ligament (PL), alveolar bone (B), osteoclast (OC). Scale bars: A, 0.2 mm; B, 0.1 mm; C, 0.05 mm.

 
Next, to determine whether differences in bone loss correlated with differences in inflammatory activity, we measured the number of inflammatory cells present in the marginal gingival tissue. The data demonstrated more intense inflammation associated with samples from the placebo-treated ligated group, consisting mainly of polymorphonuclear leukocytes (Fig. 3AGo), when compared with samples obtained from PTH-treated animals, regardless of the presence of ligature, or with placebo-treated unligated animals, where the inflammatory infiltrate was minimal (Fig. 3BGo). Statistical analysis showed that the extent of inflammatory cells around ligated teeth was significantly greater in animals from the placebo-treated ligated group when compared with the placebo-treated unligated sites or with ligated PTH-treated sites (Fig. 3CGo).




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  		Figure 3. Histological aspects of marginal gingival tissue. (A) Section around a ligated molar from the placebo-treated group, showing intense inflammatory infiltrate, consisting mainly of neutrophils. (B) Section around a ligated molar from a PTH-treated animal, showing limited inflammatory cell infiltrate. Scale bar represents 0. 05 mm. (C) Total number of inflammatory cells found in the marginal gingival tissue around molars obtained from unligated and ligated teeth from the placebo group and ligated teeth from the PTH-treated group (*p < 0.05). N = 10/group.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although PTH has been reported either to increase (catabolic effect) or to decrease (anabolic effect) osteoclastogenesis via OPG and RANKL, respectively (Simonet et al., 1997), to date, no in vivo studies have focused on the effect of intermittent PTH administration on bone loss associated with periodontal diseases. Previous studies of periodontal disease using a rodent model similar to the one used here have shown that the resulting bone loss is related to the presence of bacteria (Rovin et al., 1966). Here, using a ligature-induced periodontitis model in rodents, we show that PTH may prevent or reverse the impact of LPS and other inflammatory-associated factors on the periodontium. Since PTH receptors are present on osteoblasts and not osteoclasts, these results suggest that this protective effect is mediated through the regulation of osteoblast activity, e.g., secretion of RANKL and OPG, although PTH may also block other LPS factors involved in activation of osteoclast function. At a clinical level, analysis of the data provided here suggests that PTH, currently approved for use in treatment of osteoporosis, may also prove useful for treatment of other bone-associated diseases such as periodontal disease. In fact, bisphosphonates, another drug approved for treatment of osteoporosis, have been evaluated for use in treatment of periodontal diseases, with promising results (El-Shinnawi and El-Tantawy, 2003). Bisphosphonates are bone-sparing agents, while PTH is a bone-forming agent, and thus, PTH provides a new approach for treating bone-loss-related diseases.

PTH acts through dual signaling pathways in bone cells, with the osteoblast being the principal target. In the osteoblast, the type I PTH/PTH-related peptide receptor is coupled to both the adenylate cyclase activating G-protein-coupled protein (Gs) (cAMP/protein kinase A pathway) and the phospholipase C-activating Gq protein (Morley et al., 1997). Activaction of the Gs-mediated pathway stimulates the production of 3,5-cyclic adenosine monophosphate (cAMP), and there is evidence that this pathway is important for bone formation (Burgering et al., 1993). PTH receptor activation of the Gq-coupled pathway results in phospholipase C-mediated phosphatidylinositol hydrolysis, producing diacylglycerol (DAG), an activator of protein kinase C (PKC) isozymes (Jouishomme et al., 1994). DAG can also derive from phospholipase D (PLD)-catalyzed hydrolysis of phosphatidylcholine, and PTH stimulation of PLD activity provides another potential pathway for PKC activation in osteoblasts (Cornish et al., 1999). The dual functionality of PTH may derive from its ability to stimulate both adenylate cyclase (Spurney et al., 2002) and phospholipase C (Civitelli et al., 1998).

Overall, the activation profile of PTH in bone cells leads to induction of several growth factor genes, including those for IGF-1, IGF-2, and TGF-ß. In addition, IGFBP-1, -4, and -5 are induced by PTH, as are IGFBP protease-3 and -5 (Canalis et al., 1989; Linkhart and Mohan, 1989; Morley et al., 1997). On a cellular level, PTH enhances the recruitment of pre-osteoblasts from marrow stromal cells and induces maturation of lining osteoblasts, increasing collagen synthesis. Expression of skeletal IGF-1 is markedly enhanced in situ by PTH administration (Linkhart and Mohan, 1989).

Notwithstanding these observations, the underlying molecular physiology accounting for the true anabolic effect of PTH remains unknown. In addition, it is uncertain why intermittent, low-dose PTH administration differs so drastically in its effect on bone cells from chronic sustained PTH treatment in which catabolic effects at cortical sites predominate (Goltzman, 1999). Evidence has emerged that PTH reduces osteoblastic apoptosis, prolonging osteoblast survival and possibly potentiating its differentiated function in collagen synthesis (Jilka et al., 1999). In addition, the anabolic effect of PTH has been demonstrated in clinical trials, and there is a suggestion that the kinetics of activation/deactivation may determine whether G-protein-coupled receptor stimulation is catabolic or anabolic (Chen et al., 2002).

Osteoblast-mediated bone formation is often linked to osteoclast bone resorption. This is due, at least in part, to a balance between RANKL and OPG (Martin and Ng, 1994), both known to be released from osteoblast precursors, mature osteoblasts, PDL cells, and T-lymphocytes (Zou and Bar-Shavit, 2002). Agonists of several GPCR systems have been shown to modulate OPG and RANKL production (Swarthout et al., 2002; Zou and Bar-Shavit, 2002). Inhibition of RANKL function via the decoy receptor OPG has been shown to reduce alveolar bone destruction significantly, as reported by Teng et al.(2000). Additional studies have focused specifically on elucidating the mechanism of osteoclast generation and control in the microenvironment of the periodontium and have shown that both OPG and RANKL are present within the periodontium (Teng et al., 2000). However, it is not clear how bacteria- or endotoxin-induced bone resorption occurs. Analysis of existing data indicates that pro-inflammatory factors, e.g., cytokines, known to promote osteoclast activity, act through osteoblasts, stromal bone-lining cells, or T-lymphocytes (Teng et al., 2000). These pro-inflammatory cytokines have been shown to act synergistically with RANKL to promote osteoblast-mediated bone resorption (Chiang et al., 1999), although more recent studies suggest that factors such as LPS and TNF{alpha} may have direct effects on osteoclasts (Jiang et al., 2002; Nagasawa et al., 2002).

LPS produced by various periodontopathogens such as P. gingivalis and Actinobacillus actinomycetemcomitans induce a local inflammatory response that ultimately leads to periodontal bone resorption (Fletcher et al., 2001), but the exact mechanisms by which such micro-organisms induce bone resorption are unclear. In the periodontium, LPS may promote an inflammatory reaction through the induction of several cytokines, including IL-1, IL-6, TNF{alpha}, and prostaglandin E2 (Kondo et al., 2001; Nagasawa et al., 2002), known to be produced by several cell types, including gingival fibroblasts and recruited leukocytes (Nagasawa et al., 2002). LPS recognition requires soluble proteins [LPS-binding protein (LBP) and soluble CD14 (sCD14)] and membrane receptors [CD14 and Toll-like receptor 4 (TLR4)] (Zou and Bar-Shavit, 2002). Analysis of our data, while speculative at this point, suggests that PTH administration neutralizes LPS-mediated inflammation. In this regard, analysis of the data collected over the last decade indicates that PTH may act as an immunomodulating hormone (Doherty et al., 1988). For example, random migration of polymorphonuclear leukocytes (PMNLs) is impaired in chronic renal failure (CRF) patients, and an inverse relationship exists between random migration of PMNLs and blood levels of PTH in these patients (Doherty et al., 1988). Moreover, it is possible that PTH affects leukocyte functions directly, since both B- and T-cells contain receptors for the hormone (McCauley et al., 1992).

Taken together, these results suggest that intermittent administration of PTH may protect against bone resorption associated with periodontitis. At the clinical level, the anabolic effect of PTH on bone metabolism may represent an attractive approach for stimulating bone formation, and thus improve the outcome of periodontal therapy.


   ACKNOWLEDGMENTS
 
This work was supported by the National Council for Scientific and Technologic Development-Brazil and by NIDCR (NIH DE-09532) (to MJS).

Received December 27, 2002; Last revision June 30, 2003; Accepted July 16, 2003


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