Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis
Ano de defesa: | 2021 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | eng |
Instituição de defesa: |
Universidade Estadual Paulista (Unesp)
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Programa de Pós-Graduação: |
Não Informado pela instituição
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Departamento: |
Não Informado pela instituição
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País: |
Não Informado pela instituição
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Palavras-chave em Português: | |
Link de acesso: | http://hdl.handle.net/11449/213977 |
Resumo: | Periodontal disease (PD) is a polymicrobial chronic inflammatory condition of the supporting tissues around the teeth, leading to the destruction of surrounding connective tissue. During the progression of PD, osteoclasts play a crucial role in the resorption of alveolar bone that eventually leads to the loss of teeth if the PD is left untreated. Therefore, the development of anti-resorptive therapies targeting bone-resorbing cells will significantly benefit the treatment of PD. Here, we demonstrate the inhibitory effect of CsinCPI-2, a novel cysteine peptidase inhibitor from the orange tree, on periodontitis-induced inflammation, alveolar bone loss and osteoclast differentiation. Using the ligature-induced periodontitis model in mice, we demonstrate that treatment with CsinCPI-2 (0.8 µg/g of body weight) significantly reduced inflammatory cell infiltrate in the connective tissue and preventes the loss of alveolar bone mass (BV/TV) caused by PD, effects associated with diminished numbers of TRAP-positive multinucleated cells. Furthermore, CsinCPI-2 significantly down-regulated the numbers of inflammatory cells expressing CD3, CD45 MAC387 and IL-1β. In vitro, CsinCPI-2 inhibited RANKL-induced TRAP+ multinucleated osteoclast formation in mouse bone marrow macrophage (BMM) cultures in a concentration-dependent manner. This effect was not due to cytotoxicity, as demonstrated by the MTT assay. CsinCPI-2 inhibited RANKL-induced mRNA expression of Acp5, Calcr and Ctsk, as well as the RANKL-induced up-regulation of Nfatc1, a crucial transcription factor for osteoclast differentiation. Our findings demonstrate that CsinCPI-2 prevents bone loss induced by PD by controlling the inflammatory process and acting directly on osteoclastogenesis, suggesting an interesting potential for CsinCPI-2 in the strategy for PD treatment. |
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Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesisFitocistatina CsinCPI-2 evita a perda óssea na periodontite induzida por ligadura pela inibição da inflamação e osteoclastogêneseBonePeriodontal diseasesPeriodontitisOsteoclastInflammationOssoDoença periodontalPeriodontiteOsteoclastoInflamaçãoPeriodontal disease (PD) is a polymicrobial chronic inflammatory condition of the supporting tissues around the teeth, leading to the destruction of surrounding connective tissue. During the progression of PD, osteoclasts play a crucial role in the resorption of alveolar bone that eventually leads to the loss of teeth if the PD is left untreated. Therefore, the development of anti-resorptive therapies targeting bone-resorbing cells will significantly benefit the treatment of PD. Here, we demonstrate the inhibitory effect of CsinCPI-2, a novel cysteine peptidase inhibitor from the orange tree, on periodontitis-induced inflammation, alveolar bone loss and osteoclast differentiation. Using the ligature-induced periodontitis model in mice, we demonstrate that treatment with CsinCPI-2 (0.8 µg/g of body weight) significantly reduced inflammatory cell infiltrate in the connective tissue and preventes the loss of alveolar bone mass (BV/TV) caused by PD, effects associated with diminished numbers of TRAP-positive multinucleated cells. Furthermore, CsinCPI-2 significantly down-regulated the numbers of inflammatory cells expressing CD3, CD45 MAC387 and IL-1β. In vitro, CsinCPI-2 inhibited RANKL-induced TRAP+ multinucleated osteoclast formation in mouse bone marrow macrophage (BMM) cultures in a concentration-dependent manner. This effect was not due to cytotoxicity, as demonstrated by the MTT assay. CsinCPI-2 inhibited RANKL-induced mRNA expression of Acp5, Calcr and Ctsk, as well as the RANKL-induced up-regulation of Nfatc1, a crucial transcription factor for osteoclast differentiation. Our findings demonstrate that CsinCPI-2 prevents bone loss induced by PD by controlling the inflammatory process and acting directly on osteoclastogenesis, suggesting an interesting potential for CsinCPI-2 in the strategy for PD treatment.A doença periodontal (DP) é uma condição inflamatória polimicrobiana crônica dos tecidos de suporte ao redor dos dentes, que levam à destruição do tecido conjuntivo circundante. Durante a progressão da DP, os osteoclastos desempenham um papel crucial na reabsorção do osso alveolar que, eventualmente, leva à perda de dentes caso a DP não seja tratada. Portanto, o desenvolvimento de terapias antirreabsortivas direcionadas às células responsáveis pela reabsorção óssea irão beneficiar significativamente o tratamento da DP. Aqui demonstramos o efeito inibitório da CsinCPI-2, um novo inibidor da cisteína peptidase da laranjeira na inflamação induzida por periodontite, perda óssea alveolar e diferenciação de osteoclastos. Usando o modelo de periodontite induzida por ligadura em camundongos, demonstramos que o tratamento com CsinCPI-2 (0,8 µg / g de peso corporal) reduziu significativamente o infiltrado de células inflamatórias no tecido conjuntivo e preveniu a perda de massa óssea alveolar (BV / TV) causada pela DP, efeitos estes associados a números diminuídos de células multinucleadas TRAPpositivas. Além disso, a CsinCPI-2 regulou negativamente o número de células inflamatórias que expressam CD3, CD45 MAC387 e IL-1β. In vitro, a CsinCPI-2 inibiu a formação de osteoclastos multinucleados TRAP +, induzida por RANKL em culturas de macrófagos da medula óssea (BMM) de camundongo de uma maneira dependente da concentração. Este efeito não foi devido à citotoxicidade, conforme demonstrado pelo ensaio MTT. CsinCPI-2 inibiu a expressão de mRNA induzida por RANKL de Acp5, Calcr e Ctsk, bem como a regulação positiva induzida por RANKL de Nfatc1, um fator de transcrição crucial para a diferenciação de osteoclastos. Nossos achados demonstram que a CsinCPI-2 previne a perda óssea induzida pela DP por meio do controle do processo inflamatório e ação direta na osteoclastogênese, sugerindo um potencial interessante para a CsinCPI-2 na estratégia de tratamento da DP.OutraUniversidade Estadual Paulista (Unesp)Cirelli, Joni Augusto [UNESP]Universidade Estadual Paulista (Unesp)Da Ponte Leguizamón, Natalia2021-08-12T17:04:56Z2021-08-12T17:04:56Z2021-06-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/11449/21397733004030059P1enginfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESP2023-11-08T06:12:55Zoai:repositorio.unesp.br:11449/213977Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462023-11-08T06:12:55Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis Fitocistatina CsinCPI-2 evita a perda óssea na periodontite induzida por ligadura pela inibição da inflamação e osteoclastogênese |
title |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis |
spellingShingle |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis Da Ponte Leguizamón, Natalia Bone Periodontal diseases Periodontitis Osteoclast Inflammation Osso Doença periodontal Periodontite Osteoclasto Inflamação |
title_short |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis |
title_full |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis |
title_fullStr |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis |
title_full_unstemmed |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis |
title_sort |
Phytocystatin CsinCPI-2 prevents bone loss in ligature-induced periodontitis by inhibition of inflammation and osteoclastogenesis |
author |
Da Ponte Leguizamón, Natalia |
author_facet |
Da Ponte Leguizamón, Natalia |
author_role |
author |
dc.contributor.none.fl_str_mv |
Cirelli, Joni Augusto [UNESP] Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
Da Ponte Leguizamón, Natalia |
dc.subject.por.fl_str_mv |
Bone Periodontal diseases Periodontitis Osteoclast Inflammation Osso Doença periodontal Periodontite Osteoclasto Inflamação |
topic |
Bone Periodontal diseases Periodontitis Osteoclast Inflammation Osso Doença periodontal Periodontite Osteoclasto Inflamação |
description |
Periodontal disease (PD) is a polymicrobial chronic inflammatory condition of the supporting tissues around the teeth, leading to the destruction of surrounding connective tissue. During the progression of PD, osteoclasts play a crucial role in the resorption of alveolar bone that eventually leads to the loss of teeth if the PD is left untreated. Therefore, the development of anti-resorptive therapies targeting bone-resorbing cells will significantly benefit the treatment of PD. Here, we demonstrate the inhibitory effect of CsinCPI-2, a novel cysteine peptidase inhibitor from the orange tree, on periodontitis-induced inflammation, alveolar bone loss and osteoclast differentiation. Using the ligature-induced periodontitis model in mice, we demonstrate that treatment with CsinCPI-2 (0.8 µg/g of body weight) significantly reduced inflammatory cell infiltrate in the connective tissue and preventes the loss of alveolar bone mass (BV/TV) caused by PD, effects associated with diminished numbers of TRAP-positive multinucleated cells. Furthermore, CsinCPI-2 significantly down-regulated the numbers of inflammatory cells expressing CD3, CD45 MAC387 and IL-1β. In vitro, CsinCPI-2 inhibited RANKL-induced TRAP+ multinucleated osteoclast formation in mouse bone marrow macrophage (BMM) cultures in a concentration-dependent manner. This effect was not due to cytotoxicity, as demonstrated by the MTT assay. CsinCPI-2 inhibited RANKL-induced mRNA expression of Acp5, Calcr and Ctsk, as well as the RANKL-induced up-regulation of Nfatc1, a crucial transcription factor for osteoclast differentiation. Our findings demonstrate that CsinCPI-2 prevents bone loss induced by PD by controlling the inflammatory process and acting directly on osteoclastogenesis, suggesting an interesting potential for CsinCPI-2 in the strategy for PD treatment. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-08-12T17:04:56Z 2021-08-12T17:04:56Z 2021-06-29 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/11449/213977 33004030059P1 |
url |
http://hdl.handle.net/11449/213977 |
identifier_str_mv |
33004030059P1 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) |
publisher.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) |
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reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
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Universidade Estadual Paulista (UNESP) |
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UNESP |
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UNESP |
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Repositório Institucional da UNESP |
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Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1800401079909744640 |