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1.
J Dent Res ; 94(12): 1691-7, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26220958

ABSTRACT

Bone formation is dependent on the differentiation of osteoblasts from mesenchymal stem cells (MSCs). In addition to serving as progenitors, MSCs reduce inflammation and produce factors that stimulate tissue formation. Upon injury, MSCs migrate to the periodontium, where they contribute to regeneration. We examined the effect of clopidogrel and aspirin on MSCs following induction of periodontitis in rats by placement of ligatures. We showed that after the removal of ligatures, which induces resolution of periodontal inflammation, clopidogrel had a significant effect on reducing the inflammatory infiltrate. It also increased the number of osteoblasts and MSCs. Mechanistically, the latter was linked to increased proliferation of MSCs in vivo and in vitro. When given prior to inducing periodontitis, clopidogrel had little effect on MSC or osteoblasts numbers. Applying aspirin before or after induction of periodontitis did not have a significant effect on the parameters measured. These results suggest that clopidogrel may have a positive effect on MSCs in conditions where a reparative process has been initiated.


Subject(s)
Cell Proliferation/drug effects , Mesenchymal Stem Cells/drug effects , Periodontitis/physiopathology , Purinergic P2Y Receptor Antagonists/pharmacology , Ticlopidine/analogs & derivatives , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aspirin/pharmacology , Cell Movement/physiology , Clopidogrel , Gingiva/cytology , Gingiva/pathology , Male , Mesenchymal Stem Cells/physiology , Osteoblasts/drug effects , Osteoblasts/physiology , Periodontitis/pathology , Rats , Rats, Sprague-Dawley , Ticlopidine/pharmacology
2.
Horm Metab Res ; 46(3): 193-200, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24526374

ABSTRACT

This study evaluated the alveolar bone response to testosterone and the impact of Resolvin D2 (RvD2) on testosterone-induced osteoblast function. For the in vivo characterization, 60 male adult rats were used. Treatments established sub-physiologic (L), normal (N), or supra-physiologic (H) concentrations of testosterone. Forty rats were subjected to orchiectomy; 20 rats received periodical testosterone injections while 20 rats received testicular sham-operation. Four weeks after the surgeries, 10 rats in each group received a subgingival ligature around the lower first molars to induce experimental periodontal inflammation and bone loss. In parallel, osteoblasts were differentiated from neonatal mice calvariae and treated with various doses of testosterone for 48 h. Cell lysates and conditioned media were used for the determination of alkaline phosphatase, osteocalcin, RANKL, and osteoprotegerin. Micro-computed tomography linear analysis demonstrated that bone loss was significantly increased for both L and H groups compared to animals with normal levels of testosterone. Gingival IL-1ß expression was increased in the L group (p<0.05). Ten nM testosterone significantly decreased osteocalcin, RANKL, and OPG levels in osteoblasts; 100 nM significantly increased the RANKL:OPG ratio. RvD2 partially reversed the impact of 10 nM testosterone on osteocalcin, RANKL, and OPG. These findings suggest that both L and H testosterone levels increase inflammatory bone loss in male rats. While low testosterone predominantly increases the inflammatory response, high testosterone promotes a higher osteoblast-derived RANKL:OPG ratio. The proresolving mediator RvD2 ameliorates testosterone-derived downregulation of osteocalcin, RANKL, and OPG in primary murine osteoblasts suggesting a direct role of inflammation in osteoblast function.


Subject(s)
Bone and Bones/metabolism , Bone and Bones/pathology , Inflammation/metabolism , Inflammation/pathology , Testosterone/pharmacology , Alkaline Phosphatase/metabolism , Animals , Bone and Bones/diagnostic imaging , Bone and Bones/drug effects , Cells, Cultured , Cytokines/metabolism , Docosahexaenoic Acids/pharmacology , Down-Regulation/drug effects , Inflammation/blood , Male , Mice , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoblasts/pathology , Osteocalcin/metabolism , Osteoprotegerin/metabolism , Periodontal Diseases/blood , RANK Ligand/metabolism , Rats , Testosterone/blood , X-Ray Microtomography
3.
J Periodontal Res ; 49(6): 729-35, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24372313

ABSTRACT

BACKGROUND AND OBJECTIVE: After activation, platelets express mediators that modulate inflammation. We hypothesized that drug-induced platelet inactivation may interfere in the inflammatory process in experimental periodontal disease by suppressing the release of biological mediators to the injury site. MATERIAL AND METHODS: To evaluate the effects of antiplatelet drugs on experimental periodontal disease, 60 rats were randomly assigned to six groups (n = 10) and ligatures were placed around lower first molars in three groups. The other three groups were not subjected to the induction of periodontal disease and were used as negative controls. During the experimental period, animals were given aspirin (30 mg/kg) or clopidogrel (75 mg/kg) intragastrically once daily for 3 d. On day 3, they were killed and gingival tissue were used to evaluate myeloperoxidase activity and the expression of the chemokine CXCL4. Hemi-mandibles were used for microscopic evaluation. RESULTS: Clopidogrel significantly reduced the inflammatory infiltrate and increased the amount of collagen fibers. Histometric analysis showed that clopidogrel impaired alveolar bone loss. Expression of CXCL4 was significantly increased (p < 0.001) in rats subjected to periodontal disease. Systemic administration of aspirin and clopidogrel induced a significant decrease ( p < 0.05) in the expression of CXCL4. Treatment with antiplatelet drugs resulted in a significant reduction of myeloperoxidase activity when compared to saline-treated animals with periodontal disease. CONCLUSION: Clopidogrel but not aspirin showed the ability of preventing bone loss in experimental periodontitis.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Periodontitis/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Alveolar Bone Loss/prevention & control , Animals , Aspirin/therapeutic use , Clopidogrel , Collagen/drug effects , Connective Tissue/drug effects , Connective Tissue/pathology , Disease Models, Animal , Gingiva/drug effects , Gingiva/pathology , Inflammation Mediators/antagonists & inhibitors , Male , Mandibular Diseases/prevention & control , Periodontitis/immunology , Periodontitis/pathology , Peroxidase/analysis , Platelet Factor 4/analysis , Random Allocation , Rats , Rats, Sprague-Dawley , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic use
4.
J Periodontal Res ; 46(2): 269-79, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21306385

ABSTRACT

BACKGROUND AND OBJECTIVE: Curcumin is a plant-derived dietary spice with various biological activities, including anticarcinogenic and anti-inflammatory effects. Its therapeutic applications have been studied in a variety of conditions, including rheumatoid arthritis, colon cancer and depression, but no studies have evaluated the effects of curcumin on periodontal disease in vivo. MATERIAL AND METHODS: Experimental periodontal disease was induced in rats by placing cotton ligatures around both lower first molars. Curcumin was given to the rats by the intragastric route daily at two dosages (30 and 100 mg/kg) for 15 d. Control animals received ligatures but only the corn oil vehicle by gavage, and no treatment-negative control animals were included. Bone resorption was assessed by micro-computed tomography, and the inflammatory status was evaluated by stereometric analysis. Both RT-qPCR and ELISA were used to determine the expression of interleukin-6, tumor necrosis factor-α and prostaglandin E(2) synthase in the gingival tissues. Modulation of p38 MAPK and nuclear factor-κB activation were assessed by western blotting. RESULTS: Bone resorption was effectively induced in the experimental period, but it was not affected by either dose of curcumin. Curcumin effectively inhibited cytokine gene expression at both the mRNA and the protein level and produced a dose-dependent inhibition of the activation of nuclear factor-κB in the gingival tissues. Activation of p38 MAPK was not inhibited by curcumin. Curcumin-treated animals also presented a marked reduction of the inflammatory cell infiltrate and increased collagen content and fibroblastic cell numbers. CONCLUSION: Curcumin did not prevent alveolar bone resorption, but its potent anti-inflammatory effect suggests that it may have a therapeutic potential in periodontal diseases.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Curcumin/therapeutic use , Periodontitis/prevention & control , Alveolar Bone Loss/prevention & control , Alveolar Process/drug effects , Alveolar Process/pathology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Cell Count , Collagen/drug effects , Curcumin/administration & dosage , Cyclooxygenase 2/analysis , Dose-Response Relationship, Drug , Fibroblasts/drug effects , Gingiva/drug effects , Gingiva/pathology , Image Processing, Computer-Assisted/methods , Imaging, Three-Dimensional/methods , Inflammation , Interleukin-6/analysis , Intramolecular Oxidoreductases/analysis , Male , NF-kappa B/analysis , NF-kappa B/drug effects , Prostaglandin-E Synthases , Random Allocation , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/drug effects , X-Ray Microtomography/methods , p38 Mitogen-Activated Protein Kinases/analysis , p38 Mitogen-Activated Protein Kinases/drug effects
5.
J Periodontal Res ; 45(2): 184-92, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19778332

ABSTRACT

BACKGROUND AND OBJECTIVE: Platelets contain factors, including VEGF and endostatin, that can modulate the healing process. We evaluated the effects of severe thrombocytopenia on periodontal healing in rats and determined the contribution of VEGF and endostatin to the healing process. MATERIAL AND METHODS: Rats were distributed into three test groups and two control groups. Cotton ligatures were placed at the gingival margin level of the lower first molar in the test groups. Sham-operated rats and rats in one of the periodontitis groups were killed 15 days later. Rats in the remaining two periodontitis groups had the ligatures removed in order to study the spontaneous recovery from the periodontal disease 15 days later, and these rats were treated with rabbit antiplatelet serum, in order to induce thrombocytopenia, or normal rabbit serum. An additional group without ligatures received antiplatet serum in the same period. RESULTS: After ligature removal, rats treated with normal rabbit serum showed reduced myeloperoxidase activity, decreased alveolar bone loss and increased numbers of blood vessels. Thrombocytopenia caused a delay in alveolar bone regeneration, a decrease in the number of vessels and a modest decrease in myeloperoxidase activity. In the rats with periodontitis, serum endostatin concentrations were slightly decreased and serum VEGF remained unchanged compared with sham-operated animals. After ligature removal, a significant VEGF increase and endostatin decrease were observed in the rats treated with normal rabbit serum. Thrombocytopenia led to a dramatic fall in both VEGF and endostatin concentrations. CONCLUSION: Thrombocytopenia leads to a delay of periodontal healing in the situation of experimental periodontitis, which might be mediated in part by a decrease in the serum concentration of VEGF and endostatin derived from the platelets. However, other factors derived from the platelets may also have contributed to a delay of periodontal healing in the rats with thrombocytopenia.


Subject(s)
Angiogenesis Inhibitors/physiology , Angiogenic Proteins/physiology , Endostatins/physiology , Periodontitis/physiopathology , Thrombocytopenia/physiopathology , Vascular Endothelial Growth Factor A/physiology , Alveolar Bone Loss/pathology , Alveolar Bone Loss/physiopathology , Angiogenesis Inhibitors/blood , Angiogenic Proteins/blood , Animals , Blood Platelets/immunology , Blood Platelets/physiology , Bone Regeneration/physiology , Bone Remodeling/physiology , Endostatins/blood , Immune Sera , Male , Neovascularization, Physiologic/physiology , Periodontitis/blood , Periodontitis/pathology , Peroxidase/analysis , Platelet Count , Rabbits , Rats , Rats, Sprague-Dawley , Thrombocytopenia/blood , Time Factors , Vascular Endothelial Growth Factor A/blood , Wound Healing/physiology
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