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1.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803323

RESUMO

Periodontitis is the inflammatory destruction of the tooth-surrounding and -supporting tissue, resulting at worst in tooth loss. Another locally aggressive disease of the oral cavity is tooth resorption (TR). This is associated with the destruction of the dental mineralized tissue. However, the underlying pathomechanisms remain unknown. The complement system, as well as mast cells (MCs), are known to be involved in osteoclastogenesis and bone loss. The complement factors C3 and C5 were previously identified as key players in periodontal disease. Therefore, we hypothesize that complement factors and MCs might play a role in alveolar bone and tooth resorption. To investigate this, we used the cat as a model because of the naturally occurring high prevalence of both these disorders in this species. Teeth, gingiva samples and serum were collected from domestic cats, which had an appointment for dental treatment under anesthesia, as well as from healthy cats. Histological analyses, immunohistochemical staining and the CH-50 and AH-50 assays revealed increased numbers of osteoclasts and MCs, as well as complement activity in cats with TR. Calcifications score in the gingiva was highest in animals that suffer from TR. This indicates that MCs and the complement system are involved in the destruction of the mineralized tissue in this condition.


Assuntos
Perda do Osso Alveolar/metabolismo , Complemento C3/metabolismo , Complemento C5/metabolismo , Mastócitos/metabolismo , Periodontite/metabolismo , Reabsorção de Dente/metabolismo , Perda do Osso Alveolar/patologia , Animais , Gatos , Mastócitos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Periodontite/patologia , Reabsorção de Dente/patologia
3.
Life Sci ; 269: 119073, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33460666

RESUMO

AIMS: Coagulation is a common event that play a double-edged role in physiological and pathological process. Anti-coagulation methods were applied in joint surgery or scaffolds implantation to encourage new vascular formation and avoid coagulation block. However, whether anti-coagulation drug perform regulatory roles in bone structure is unknown. This study aims to explore a direct thrombin inhibitor, argatroban, effects on bone marrow stromal cells (BMSCs) and decipher the underlying mechanisms. MATERIALS AND METHODS: Argatroban effects on BMSCs were investigated in vivo and in vitro. The drug was applied in periodontal disease model mice and bone loss was evaluated by µCT and histology. BMSCs were treated with different doses argatroban or vehicle. Cellular reactions were analyzed using wound healing assay, qRT-PCR, Alizarin Red S staining and western blotting. KEY FINDINGS: We demonstrated that local injection of argatroban can rescue bone loss in periodontal disease in vivo. To explore the underlying mechanism, we examined that cell proliferation and differentiation capability. Proliferation and migration of BMSCs were both inhibited by applying lower dose of argatroban. Interestingly, without affecting osteoclastogenesis, osteogenic differentiation was significantly induced by argatroban, which were shown by extracellular mineralization and upregulation of early osteoblastic differentiation markers, alkaline phosphatase, Osteocalcin, transcription factors RUNX2 and Osterix. In addition, molecular analysis revealed that argatroban promoted ß-catenin nuclear translocation and led to an increase of osteogenesis through activating canonical Wnt signaling. SIGNIFICANCE: Taken together, our results show the novel application of the anti-coagulation compound argatroban in the commitment of BMSCs-based alveolar bone regeneration and remodeling.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Arginina/análogos & derivados , Células-Tronco Mesenquimais/citologia , Osteogênese , Periodontite/complicações , Ácidos Pipecólicos/farmacologia , Sulfonamidas/farmacologia , Trombina/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Animais , Antitrombinas/farmacologia , Arginina/farmacologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
4.
Cell Prolif ; 54(2): e12973, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33382502

RESUMO

OBJECTIVES: NLRP3 inflammasome is a critical part of the innate immune system and plays an important role in a variety of inflammatory diseases. However, the effects of NLRP3 inflammasome on periodontitis have not been fully studied. MATERIALS AND METHODS: We used ligature-induced periodontitis models of NLRP3 knockout mice (NLRP3KO ) and their wildtype (WT) littermates to compare their alveolar bone phenotypes. We further used Lysm-Cre/RosanTnG mouse to trace the changes of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis with or without MCC950 treatment. At last, we explored MCC950 as a potential drug for the treatment of periodontitis in vivo and in vitro. RESULTS: Here, we showed that the number of osteoclast precursors, osteoclast differentiation and alveolar bone loss were reduced in NLRP3KO mice compared with WT littermates, by using ligature-induced periodontitis model. Next, MCC950, a specific inhibitor of the NLRP3 inflammasome, was used to inhibit osteoclast precursors differentiation into osteoclast. Further, we used Lysm-Cre/RosanTnG mice to demonstrate that MCC950 decreases the number of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis. At last, treatment with MCC950 significantly suppressed alveolar bone loss with reduced IL-1ß activation and osteoclast differentiation in ligature-induced periodontitis. CONCLUSION: Our findings reveal that NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation.


Assuntos
Perda do Osso Alveolar/patologia , Diferenciação Celular , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoclastos/citologia , Periodontite/patologia , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/prevenção & controle , Animais , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Periodontite/tratamento farmacológico , Periodontite/etiologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Sulfonas/farmacologia , Sulfonas/uso terapêutico
5.
Molecules ; 25(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321702

RESUMO

The aim of this study was to assess the effect of local application of essential oil of Pistacia atlantica kurdica (EOK) gel in treatment of experimentally induced periodontitis in rats and its effect on osteoclastogenic bone markers. Twenty-four male Wistar rats of 250 to 350 g were used in this study and were allocated into four groups. Control negative (without induced periodontitis), control positive (induced experimental periodontitis left without treatment), treatment control (induced experimental periodontitis and treated with Chlorhexidine gel) and EOK treated group (induced experimental periodontitis treated with EOK gel). The animals were sacrificed after 30 days, and the mandibular central incisor and surrounding tissue were dissected from the mandible and further processed for preparing H&E slides. Inflammatory cells, osteoclast cells, and periodontal ligament (PDL) were examined and measured histologically. Finally, the mean concentrations of both markers, receptor activator of nuclear factor kappa-Β ligand (RANKL) and (Interleukin-1ß) IL-1ß, were analyzed by ELISA. A significant reduction of inflammatory reaction and osteoclast numbers with improvement of PDL and low mean concentrations of RANKL and IL-1ß were seen in the EOK treated group in comparison to the control group and the chlorhexidine group as well. The extract showed a protective effect in the healing of periodontitis that had been induced in rats and decreased bone resorption by down regulation of serum RANKL and IL-1ß markers.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Biomarcadores , Osteoclastos/metabolismo , Periodontite/metabolismo , Pistacia/química , Gomas Vegetais/química , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cromatografia Gasosa-Espectrometria de Massas , Imuno-Histoquímica , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Ligamento Periodontal/patologia , Periodontite/tratamento farmacológico , Periodontite/etiologia , Ratos
6.
Acta Odontol Latinoam ; 33(2): 143-152, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920617

RESUMO

The aims of the present study were, first, to identify signs of alveolar bone damage in early stages of experimental periodontitis (EP) and, second, to assess its possible prevention by treatment with cannabinoid receptor 2 agonist HU 308. Experimental periodontitis was induced by injections of lipopolysaccharide (LPS) (1mg/ml) in gums surrounding maxillary and mandibular first molar, 3 days per week, and untreated controls were kept for comparison. Then, a 3-week study was conducted including eighteen new rats (six rats per group): 1) controls; 2) experimental periodontitis rats; and 3) experimental periodontitis rats treated daily with HU 308 (500 ng/ml). After euthanasia, alveolar bone loss was assessed by morphometric and histomorphometric techniques, and the content of prostaglandin E2 (PGE2) in gingival tissue was evaluated by radioimmunoassay. The first signs of alveolar bone loss were apparent at 3 weeks of experimental periodontitis (ρ<0.05) in the mandibular first molar, but there was no detectable change at 1 week, leading us to establish 3 weeks as an early stage of experimental periodontitis. Rats subjected to 3-week experimental periodontitis showed less interradicular bone volume, less whole bone perimeter and fewer bone formation areas, and higher periodontal space height, bone resorption areas, number of osteoclasts and gingival content of prostaglandin E2 than controls, while HU 308 prevented, at least partially, the deleterious effects (ρ<0.001). We can conclude that a 3-week term of lipopolysaccharide-induced periodontitis in rats provides a valid model of the early stage of the disease, as emerging damage is observed in bone tissue. Furthermore, harmful effects at 3 weeks could be prevented by local stimulation of cannabinoid receptor 2, before greater damage is produced.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Osso e Ossos/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Periodontite , Perda do Osso Alveolar/metabolismo , Animais , Modelos Animais de Doenças , Osteoclastos , Periodontite/metabolismo , Periodontite/prevenção & controle , Ratos
7.
PLoS One ; 15(8): e0237660, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841254

RESUMO

This study evaluated the influence of type 2 diabetes mellitus on bone loss, bone repair and cytokine production in hyperglycemic rats, treated or not with metformin. The animals were distributed as follow: Non-Hyperglycemic (NH), Non Hyperglycemic with Ligature (NH-L), Treated Non Hyperglycemic (TNH), Treated Non Hyperglycemic with Ligature Treated (TNH-L), Hyperglycemic (H), Treated Hyperglycemic (TH), Hyperglycemic with Ligature (H-L), Treated Hyperglycemic with Ligature (TH-L). At 40th day after induction of hyperglycemia, the groups NH-L, TNH-L, H-L, TH-L received a ligature to induce periodontitis. On the 69th, the TNH, TNH-L, TH, TH-L groups received metformin until the end of the study. Bone repair was evaluated at histometric and the expression levels of Sox9, RunX2 and Osterix. Analysis of the ex-vivo expression of TNF-α, IFN-γ, IL-12, IL-4, TGF-ß, IL-10, IL-6 and IL-17 were also evaluated. Metformin partially reverse induced bone loss in NH and H animals. Lower OPG/RANKL, increased OCN and TRAP expression were observed in hyperglycemic animals, and treatment with metformin partially reversed hyperglycemia on the OPG/RANKL, OPN and TRAP expression in the periodontitis. The expression of SOX9 and RunX2 were also decreased by hyperglycemia and metformin treatment. Increased ex vivo levels of TNF-α, IL-6, IL-4, IL-10 and IL-17 was observed. Hyperglycemia promoted increased IL-10 levels compared to non-hyperglycemic ones. Treatment of NH with metformin was able to mediate increased levels of TNF-α, IL-10 and IL-17, whereas for H an increase of TNF-α and IL-17 was detected in the 24- or 48-hour after stimulation with LPS. Ligature was able to induce increased levels of TNF-α and IL-17 in both NH and H. This study revealed the negative impact of hyperglycemia and/or treatment with metformin in the bone repair via inhibition of transcription factors associated with osteoblastic differentiation.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Hiperglicemia/complicações , Metformina/administração & dosagem , Periodontite/prevenção & controle , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , Processo Alveolar/citologia , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/metabolismo , Processo Alveolar/patologia , Animais , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/genética , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Osteoblastos/fisiologia , Periodontite/etiologia , Periodontite/metabolismo , Ratos , Estreptozocina/toxicidade , Fatores de Transcrição/metabolismo
8.
J Pathol ; 251(3): 323-335, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32418202

RESUMO

The lymphatic system plays a crucial role in the maintenance of tissue fluid homeostasis and the immunological response to inflammation. The effects of lymphatic drainage dysfunction on periodontitis have not been well studied. Here we show that lymphatic vessel endothelial receptor 1 (LYVE1)+ /podoplanin (PDPN)+ lymphatic vessels (LVs) are increased in the periodontal tissues, with accumulation close to the alveolar bone surface, in two murine periodontitis models: rheumatoid arthritis (RA)-associated periodontitis and ligature-induced periodontitis. Further, PDPN+ /alpha-smooth muscle actin (αSMA)- lymphatic capillaries are increased, whereas PDPN+ /αSMA+ collecting LVs are decreased significantly in the inflamed periodontal tissues. Both mouse models of periodontitis have delayed lymph flow in periodontal tissues, increased TRAP-positive osteoclasts, and significant alveolar bone loss. Importantly, the local administration of adeno-associated virus for vascular endothelial growth factor C, the major growth factor that promotes lymphangiogenesis, increases the area and number of PDPN+ /αSMA+ collecting LVs, promotes local lymphatic drainage, and reduces alveolar bone loss in both models of periodontitis. Lastly, LYVE1+ /αSMA- lymphatic capillaries are increased, whereas LYVE1+ /αSMA+ collecting LVs are decreased significantly in gingival tissues of patients with chronic periodontitis compared with those of clinically healthy controls. Thus, our findings reveal an important role of local lymphatic drainage in periodontal inflammation-mediated alveolar bone loss. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Processo Alveolar/metabolismo , Periodontite Crônica/terapia , Terapia Genética , Linfa/metabolismo , Vasos Linfáticos/metabolismo , Maxila/metabolismo , Fator C de Crescimento do Endotélio Vascular/biossíntese , Fator C de Crescimento do Endotélio Vascular/genética , Perda do Osso Alveolar/genética , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Processo Alveolar/patologia , Animais , Estudos de Casos e Controles , Periodontite Crônica/genética , Periodontite Crônica/metabolismo , Periodontite Crônica/patologia , Modelos Animais de Doenças , Humanos , Vasos Linfáticos/patologia , Masculino , Maxila/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoclastos/metabolismo , Osteoclastos/patologia , Fator de Necrose Tumoral alfa/genética
9.
Artigo em Inglês | MEDLINE | ID: mdl-32179099

RESUMO

We previously detected a submicromolar concentration of lysophosphatidic acid (LPA) in human saliva. Here, we compare LPA concentrations in human gingival crevicular fluid (GCF) from patients with periodontitis and healthy controls, and examine how the local LPA levels are regulated enzymatically. The concentrations of LPA and its precursor lysophospholipids in GCF was measured by liquid chromatography-tandem mass spectrometry. The LPA-producing and LPA-degrading enzymatic activities were measured by quantifying the liberated choline and free fatty acid, respectively. The concentration of LPA in GCF of periodontitis patients was lower than that of healthy controls, due to higher soluble lysophospholipase activity toward LPA. LPA was found to prevent survival of Sa3, a human gingival epithelium-derived tumor cell line, activate Sa3 through Ca2+ mobilization, and release interleukin 6 from Sa3 in vitro. Furthermore, local injection of LPA into the gingiva attenuated ligature-induced experimental alveolar bone loss induced by oral bacteria inoculation in a rat model of periodontitis in vivo. A high concentration of LPA in human GCF is necessary to maintain normal gingival epithelial integrity and function, protecting the progression of periodontitis.


Assuntos
Perda do Osso Alveolar/metabolismo , Líquido do Sulco Gengival/metabolismo , Lisofosfolipase/metabolismo , Lisofosfolipídeos/metabolismo , Periodontite/metabolismo , Adulto , Idoso , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/prevenção & controle , Animais , Células Cultivadas , Feminino , Humanos , Lisofosfolipídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Periodontite/tratamento farmacológico , Ratos , Ratos Wistar
10.
Cell Prolif ; 53(4): e12800, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32215984

RESUMO

OBJECTIVES: The aim of this study was to investigate the role of p75 neurotrophin receptor (p75NTR) in regulating the mouse alveolar bone development and the mineralization potential of murine ectomesenchymal stem cells (EMSCs). Moreover, we tried to explore the underlying mechanisms associated with the PI3K/Akt/ß-catenin pathway. MATERIALS AND METHODS: p75NTR knockout (p75NTR-/- ) mice and wild-type (WT) littermates were used. E12.5d p75NTR-/- and WT EMSCs were isolated in the same pregnant p75NTR-/+ mice from embryonic maxillofacial processes separately. Mouse alveolar bone mass was evaluated using micro-CT. Differential osteogenic differentiation pathways between p75NTR-/- and WT EMSCs were analysed by RNA-sequencing. The PI3K inhibitor LY294002 and PI3K agonist 740Y-P were used to regulate the PI3K/Akt pathway in EMSCs. p75NTR overexpression lentiviruses, p75NTR knock-down lentiviruses and recombined mouse NGF were used to transfect cells. RESULTS: The alveolar bone mass was found reduced in the p75NTR knockout mouse comparing to the WT mouse. During mineralization induction, p75NTR-/- EMSCs displayed decreased osteogenic capacity and downregulated PI3K/Akt/ß-catenin signalling. The PI3K/Akt/ß-catenin pathway positively regulates the potential of differential mineralization in EMSCs. The promotive effect of p75NTR overexpression can be attenuated by LY294002, while the inhibitory effect of p75NTR knock-down on Runx2 and Col1 expression can be reversed by 740Y-P. CONCLUSION: Deletion of p75NTR reduced alveolar bone mass in mice. P75NTR positively regulated the osteogenic differentiation of EMSCs via enhancing the PI3K/Akt/ß-catenin pathway.


Assuntos
Perda do Osso Alveolar/genética , Doenças Mandibulares/genética , Receptores de Fator de Crescimento Neural/genética , Transdução de Sinais , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Animais , Células Cultivadas , Deleção de Genes , Masculino , Doenças Mandibulares/metabolismo , Doenças Mandibulares/patologia , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , beta Catenina/metabolismo
11.
Sci Rep ; 10(1): 1850, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024893

RESUMO

Platelet-rich fibrin (PRF) provides a scaffold for cell migration and growth factors for promoting wound healing and tissue regeneration. Here, we report using PRF in periodontal healing after open flap debridement (OFD) in canine periodontitis. A split-mouth design was performed in twenty dogs. Forty periodontitis surgical sites were randomly categorized into 2 groups; OFD alone and OFD with PRF treatment. Clinical parameters of periodontal pocket depth, gingival index, and the cemento-enamel junction-alveolar bone levels/root length ratio were improved in the OFD + PRF group. The OFD + PRF group also demonstrated a dramatically decreased inflammatory score compared with the OFD group. Collagen accumulation was improved in the OFD + PRF group at later time points compared with baseline. PRF application also significantly reduced inflammatory cytokine expression (TNFA and IL1B), and promoted the expression of collagen production-related genes (COL1A1, COL3A1, and TIMP1) and growth factors (PDGFB, TGFB1, and VEGFA). These findings suggest that PRF combined with OFD provides a new strategy to enhance the overall improvement of canine periodontitis treatment outcomes, especially in terms of inflammation and soft tissue healing. Therefore, PRF use in treating periodontitis could play an important role as a regenerative material to improve canine periodontitis treatment.


Assuntos
Periodontite Crônica/metabolismo , Fibrina/farmacologia , Bolsa Periodontal/tratamento farmacológico , Bolsa Periodontal/metabolismo , Fibrina Rica em Plaquetas/metabolismo , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/metabolismo , Animais , Citocinas/metabolismo , Desbridamento/métodos , Cães , Genes Reguladores/genética , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Índice Periodontal , Retalhos Cirúrgicos/fisiologia , Resultado do Tratamento , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia
12.
Cell Prolif ; 53(2): e12743, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943455

RESUMO

OBJECTIVES: Alveolar bone osteoporosis has attracted more and more attention because of its profound impact on stomatognathic function and treatment, but current treatments have not been targeted to alveolar bone and might even cause severe side effects. Thus, identifying the effects of anti-osteoporosis agents on alveolar bone is essential. Icariin ameliorates metabolic dysfunction of long bones, but its effects on alveolar bone remain unclarified. MATERIALS AND METHODS: BMSCs were isolated from rat mandibles (mBMSCs). The osteogenic potential of mBMSCs and the signalling pathway involved under icariin treatment were measured by ALP and alizarin red staining, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence. Dual-luciferase assay, chromatin immunoprecipitation (ChIP) and co-immunoprecipitation were used to investigate the molecular mechanism. Ovariectomized and sham-operated rats treated with or without icariin were analysed by micro-CT, TRAP staining and calcein double labelling. RESULTS: We found that icariin promoted osteoblast differentiation of mBMSCs. Furthermore, STAT3 was critical for icariin-promoted osteoblast differentiation, as indicated by increased phosphorylation levels in icariin-treated mBMSCs, while preventing STAT3 activation blocked icariin-induced osteoblast differentiation. Mechanistically, icariin-promoted transcription of the downstream osteogenic gene osteocalcin (Ocn) through STAT3 and STAT3 bound to the promoter of Ocn. Notably, icariin prevented the alveolar bone osteoporosis induced by oestrogen deficiency through promoting bone formation. CONCLUSIONS: For the first time, our work provides evidence supporting the potential application of icariin in promoting osteogenesis and treating alveolar bone osteoporosis.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Estrogênios/metabolismo , Flavonoides/farmacologia , Osteogênese/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Perda do Osso Alveolar/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/efeitos dos fármacos , Osteocalcina/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
13.
Inflammation ; 43(1): 220-230, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31720989

RESUMO

Periodontitis is an inflammation characterized by alveolar bone resorption caused by imbalance in bone homeostasis. It is known that autophagy is related to inflammation and bone metabolism. However, whether autophagy inhibitors could be used for periodontitis in animal models remains unknown. We investigated the role of two classical autophagy inhibitors, 3-methyladenine (3-MA) and chloroquine (CQ), on the development of rat experimental periodontitis in terms of the bone loss (micro-CT), the number of inflammatory cells (hematoxylin and eosin staining), and the osteoclastic activity (tartrate-resistant acid phosphatase staining). Expression of autophagy-related genes and nuclear factor kappa B p65 (NF-κB p65) were assessed by immunohistochemistry. Expression of Beclin-1 and microtubule-associated proteins 1A/1B light chain 3 (LC3) were analyzed by Western blot. To further observe the effect of autophagy inhibitors on osteoclasts (OCs) in vitro, bone marrow-derived mononuclear macrophages were used. Together, these findings indicated that topical administration of 3-MA or CQ reduced the infiltration of inflammatory cells and alveolar bone resorption in experimental periodontitis. Furthermore, 3-MA and CQ may attenuate activation of OCs by autophagy. Therefore, 3MA and CQ may have prophylactic and therapeutic potential for inflammation and alveolar bone resorption in periodontitis in the future.


Assuntos
Adenina/análogos & derivados , Perda do Osso Alveolar/prevenção & controle , Processo Alveolar/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Cloroquina/farmacologia , Osteoclastos/efeitos dos fármacos , Periodontite/prevenção & controle , Adenina/farmacologia , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/microbiologia , Perda do Osso Alveolar/patologia , Processo Alveolar/metabolismo , Processo Alveolar/microbiologia , Processo Alveolar/patologia , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Masculino , Osteoclastos/metabolismo , Osteoclastos/microbiologia , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Periodontite/metabolismo , Periodontite/microbiologia , Periodontite/patologia , Porphyromonas gingivalis , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo
14.
Sci Rep ; 9(1): 19257, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848404

RESUMO

Periodontitis is a prevalent chronic inflammatory disease due to the host response (IL-1ß, IL-6, TNF-α and IL-17A) to oral bacteria such as Porphyromonas gingivalis. The newer members of the IL-1 family, IL-36s (IL-36α/IL-36ß/IL-36γ/IL-36Ra/IL-38) are known to be involved in host defense against P. gingivalis in oral epithelial cells (OECs) and are considered as key inflammatory mediators in chronic diseases. The aim of this study was to investigate the potential role of IL-36s in periodontitis. We showed here that IL-36γ mRNA gingival expression is higher in periodontitis patients, whereas IL-36ß and IL-36Ra mRNA expression are lower compared to healthy controls. Interestingly, the elevated IL-36γ expression in patients is positively correlated with the RANKL/OPG ratio, an index of bone resorption. In vitro, IL-36γ expression was induced through TLR2 activation in primary OECs infected with P. gingivalis but not in gingival fibroblasts, the most widespread cell type in gingival connective tissue. In OECs, recombinant IL-36γ enhanced the expression of inflammatory cytokines (IL-1ß, IL-6, TNF-α and IL-36γ), of TLR2 and importantly, the RANKL/OPG ratio. These findings suggest that IL-36γ could be a pivotal inflammatory player in periodontitis by perpetuating gingival inflammation and its associated alveolar bone resorption and could be a relevant therapeutic target.


Assuntos
Perda do Osso Alveolar , Infecções por Bacteroidaceae , Interleucina-1/metabolismo , Periodontite , Porphyromonas gingivalis/metabolismo , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/microbiologia , Perda do Osso Alveolar/patologia , Infecções por Bacteroidaceae/metabolismo , Infecções por Bacteroidaceae/patologia , Linhagem Celular , Feminino , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Masculino , Periodontite/metabolismo , Periodontite/microbiologia , Periodontite/patologia
15.
Biomed Res Int ; 2019: 6712591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886238

RESUMO

Phosphatase and tensin homolog (PTEN) is a critical regulator of tumorigenesis and bone remodeling, which is also found expressed in the periodontal tissues. Periodontitis is one of the most common oral diseases and associated with alveolar bone resorption and tooth loosening in adults. However, the functional relevance of PTEN in periodontitis remains unclear. Here, we report that PTEN plays an essential role in periodontitis. The in vivo results of our study showed a significant decrease of PTEN in the ligature-induced mouse periodontitis model. The function of PTEN in the macrophages was shown to be associated with inflammatory factors interleukin 1 (IL1) and tumor necrosis factor (TNF-α) by using overexpression and silence methods. Further mechanistic studies indicated lack of PTEN-activated IL1 and TNF-α, which increased the number of osteoclasts and led to alveolar bone erosion and loss. Moreover, PTEN nanoparticles could directly inhibit the inflammatory process and bone erosion, suggesting a controlling role of PTEN during bone remodeling. All these data identified the novel function of PTEN as a key factor in periodontitis and bone remodeling.


Assuntos
Perda do Osso Alveolar/metabolismo , PTEN Fosfo-Hidrolase , Periodontite/metabolismo , Animais , Remodelação Óssea/fisiologia , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Oxid Med Cell Longev ; 2019: 1529520, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485288

RESUMO

Aim: To investigate whether methylene blue-mediated photodynamic therapy (MB-PDT) can affect the "fate" of macrophages in vitro or in periodontitis tissues and to explore the potential mechanism. Methods: For in vitro treatments, THP-1 macrophages were divided into three experimental groups: C/control, no treatment; MB, methylene blue treatment; and MB-PDT, MB and laser irradiation treatment. Then, apoptosis and apoptosis-related proteins were detected in each group. For in vivo treatments, periodontitis was ligature-induced in the first molars of the bilateral maxilla in 12 Sprague Dawley (SD) rats. After six weeks, the ligatures were removed and all the induced molars underwent scaling and root planning (SRP). Then, the rats were divided into three groups according to the following treatments: SRP, saline solution; MB, phenothiazinium dye; and MB-PDT, MB and laser irradiation. Apoptotic macrophages, inflammation levels, and alveolar bone resorption in the periodontal tissues of rats were analyzed in each group. Results: In vitro, flow cytometry analysis demonstrated that 10 µM MB and 40 J/cm2 laser irradiation maximized the apoptosis rate (34.74%) in macrophages. Fluorescence probe and Western blot analyses showed that MB-PDT induced macrophage apoptosis via reactive oxygen species (ROS) and the mitochondrial-dependent apoptotic pathway. Conversely, the addition of exogenous antioxidant glutathione (GSH) and the pan-caspase inhibitor Z-VAD-FMK markedly reduced the apoptotic response in macrophages. In vivo, immunohistochemistry, histology, radiographic, and molecular biology experiments revealed fewer infiltrated macrophages, less bone loss, and lower IL-1ß and TNF-α levels in the MB-PDT group than in the SRP and MB groups (P < 0.05). Immunohistochemistry analysis also detected apoptotic macrophages in the MB-PDT group. Conclusion: MB-PDT could induce macrophage apoptosis in vitro and in rats with periodontitis. This may be another way for MB-PDT to relieve periodontitis in addition to its antimicrobial effect. Meanwhile, MB-PDT induced apoptosis in THP-1 macrophages via the mitochondrial caspase pathway.


Assuntos
Perda do Osso Alveolar/metabolismo , Macrófagos/metabolismo , Periodontite/terapia , Fotoquimioterapia/métodos , Animais , Apoptose , Masculino , Azul de Metileno , Periodontite/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio
17.
Med Sci Monit ; 25: 6104-6109, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31414668

RESUMO

BACKGROUND Smoking may be a risk factor for marginal bone loss (MBL) and oral mucosal inflammation surrounding dental implants. This retrospective study evaluated the effects of smoking on dental implants in patients with fixed implant-supported prostheses over a period of 36 months following loading. MATERIAL AND METHODS We assessed 120 patients (68 women, 52 men, ages 19-74 years (mean age: 55.10 years) with 315 implants. Implants were classified according to location in the upper and lower jaws and anterior (placed between canines) or posterior (placed between pre-molars and molars) as follows: 1=maxilla anterior, 2=maxilla posterior, 3=mandible anterior, 4=mandible posterior. We also measured MBL, plaque index (PI), sulcus bleeding index (SBI), and probing depth (PD). P-values less than 0.05 were considered statistically significant. RESULTS MBL was statistically greater in smokers (P<0.001) as compared to non-smokers in both jaws. MBL did not vary significantly by location in either group (smokers: p=0.415; non-smokers: p=0.175). Mean PI and PD scores were significantly higher in smokers as compared to non-smokers (P<0.001). A positive correlation was found between PI and PD scores in both groups. No statistically significant difference in SBI was observed between the 2 groups (P>0.05). CONCLUSIONS Smoking was associated with increases in marginal bone loss around implants, independent of their location in the jaws. Also, both plaque indices and probing depths were greater in smokers than in non-smokers.


Assuntos
Perda do Osso Alveolar/etiologia , Fumar Cigarros/efeitos adversos , Adulto , Idoso , Perda do Osso Alveolar/metabolismo , Implantes Dentários , Índice de Placa Dentária , Prótese Dentária Fixada por Implante , Feminino , Seguimentos , Humanos , Masculino , Mandíbula , Doenças Mandibulares/etiologia , Pessoa de Meia-Idade , Índice Periodontal , Estudos Retrospectivos , Fumantes
18.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 54(6): 420-424, 2019 Jun 09.
Artigo em Chinês | MEDLINE | ID: mdl-31177684

RESUMO

Periodontal disease (PD) is an infection-driven chronic inflammatory disease characterized by the inflammation of tooth-supporting tissues and the destruction of the associated alveolar bone. The immune response of the host to periodontal pathogens infection determines the course and progress of the disease. The effects of secreting cytokines interferon-gamma (IFN-γ) and interleukin-17 (IL-17) of T helper 1 cells (Th1) and T helper 17 cells (Th17) on the development of periodontitis has attracted much attention. IFN-γ is a potential immune-modulatory cytokine and can mediate cellular immune responses by activating various immune cells of the host such as macrophages. As one of the most potential bone physiological regulation mediators, IL-17 is closely related with alveolar bone resorption in periodontitis. This review elaborated the relationship between IFN-γ and IL-17 in the progress of periodontitis, providing new explanations into the development of periodontitis and alveolar bone destruction caused by the host immune response.


Assuntos
Perda do Osso Alveolar , Interferon gama , Interleucina-17 , Periodontite , Perda do Osso Alveolar/imunologia , Perda do Osso Alveolar/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Periodontite/imunologia , Periodontite/metabolismo , Células Th1 , Células Th17
19.
J Orthop Surg Res ; 14(1): 167, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146750

RESUMO

BACKGROUND: Excessive inflammatory response under hyperglycemia can impair alveolar bone defect healing under diabetic conditions. NLRP3 (NACHT [nucleotide-binding oligomerization], LRR [leucine-rich repeat], and PYD [pyrin domain] domains-containing protein 3) inflammasome has been considered to play a crucial role in the inflammatory response, but its correlation with the impaired alveolar bone repair in diabetes still remains unclarified. The objective of the current study is to investigate the effect of NLRP3 inflammasome inhibition by a lentiviral short hairpin RNA (shRNA) targeting NLRP3 on alveolar bone defect healing in diabetic rats. METHODS: Diabetes was induced in rats by high-fat diet and streptozotocin injection, and alveolar bone defects in both maxillae were created by surgery. Then, the lentiviral shRNA targeting NLRP3 was applied in the defect. Eight weeks after surgery, the alveolar bone regeneration was examined using hematoxylin and eosin (H&E) staining, and the gene expression in the bone healing site was detected using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis and western blot analysis. RESULTS: H&E staining showed that treatment with lentiviral shRNA targeting NLRP3 could increase the bone regeneration score in the alveolar bone defect of diabetic rats. Additionally, qRT-PCR analysis and western blot analysis of the bone defect demonstrated that this shRNA inhibited the expression of NLRP3, apoptosis-associated speck-like protein containing a CARD, caspase-1, and proinflammatory cytokine interleukin-1ß and increased the expression of osteogenic markers Runt-related transcription factor 2 and osteocalcin. CONCLUSIONS: Our findings suggested that inhibition of NLRP3 inflammasome could improve alveolar bone defect healing in diabetic rats. The beneficial effect may correlate with reduced proinflammatory cytokine production and increased osteogenic gene expression in hyperglycemia.


Assuntos
Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Perda do Osso Alveolar/tratamento farmacológico , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Masculino , RNA Interferente Pequeno/administração & dosagem , Ratos , Ratos Wistar
20.
Biomed Res Int ; 2019: 8528719, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949512

RESUMO

Aim: Cyclophilin A (CypA)/CD147 signaling plays critical roles in the regulation of inflammation and bone metabolism. This study aimed to investigate the participation of CypA/CD147 in mice periapical lesions progression and its relationship with bone resorption. Methodology: Periapical lesions were induced by pulp exposure in the first lower molars of 40 C57BL/6J mice. The mice were sacrificed on days 0, 7, 14, 21, 28, 35, 42, and 49. Mandibles were harvested for X-ray imaging, microcomputed tomography scanning, histologic observation, immunohistochemistry, enzyme histochemistry, and double immunofluorescence analysis. Western blot was employed to further detect the related molecular signaling pathways in LPS-stimulated RAW 264.7 cells treated with CypA inhibitor. Results: The volume and area of the periapical lesions increased from day 0 to day 35 and remained comparably stable until day 49. Immunohistochemistry demonstrated that the CypA expression levels also increased from day 0 to day 35 and decreased until day 49, similar to CD147 expression (R 2 = 0.4423, P < 0.05), osteoclast number (R 2 = 0.5101, P < 0.01), and the expression of osteoclastogenesis-related matrix metalloproteinase 9 (MMP-9) (R 2 = 0.4715, P < 0.05). Serial sections further confirmed the colocalization of CypA and CD147 on osteoclasts with immunohistochemistry. And the distribution of CypA-positive or CD147-positive cells was positively correlated with the dynamics of MMP-9-positive cells by using immunofluorescence analysis. Furthermore, CD147 and MMP-9 expression in RAW 264.7 cells were both downregulated with CypA inhibitor treatment (P < 0.05). Conclusions: The present study reveals the positive correlation of CypA/CD147 signaling and osteoclast-related MMP-9 expression in mice inflammatory periapical lesions progression. Therefore, intervention of CypA/CD147 signaling could probably provide a potential therapeutic target for attenuating inflammatory bone resorption.


Assuntos
Perda do Osso Alveolar/metabolismo , Basigina/metabolismo , Ciclofilina A/metabolismo , Regulação Enzimológica da Expressão Gênica , Metaloproteinase 9 da Matriz/biossíntese , Dente Molar/metabolismo , Transdução de Sinais , Perda do Osso Alveolar/induzido quimicamente , Perda do Osso Alveolar/patologia , Animais , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Dente Molar/patologia , Células RAW 264.7
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