Processo de reparo alveolar frente à administração de bifosfonato nitrogenado: avaliação comparativa em camundongos 129/Sv-WT e 129/Sv 5-LOKO
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Data
2022-08-26
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Universidade Estadual Paulista (Unesp)
Resumo
A instalação das osteonecroses dos maxilares (OM) tem sido relacionada ao uso crônico de medicamentos antirreabsortivos indicados para doenças e distúrbios do metabolismo ósseo, como os bifosfonatos nitrogenados (nBF). Deste modo, especula-se que a instalação desta doença não ocorre somente devido à condição do tecido ósseo e sua capacidade reacional, mas principalmente pela sua condição de defesa imunológica. O presente estudo tem como objetivo analisar o padrão de reparo ósseo de alvéolos dentários de incisivos superiores recém-extraídos de camundongos 129/Sv geneticamente modificados (knockouts – KO) para a enzima 5-lipoxigenase (5-LO), os quais apresentam fenótipo esqueletal osteopetrótico, comparando-os com tipo selvagem (Wild Type – WT), com e sem administração de nBF. Para tanto foram utilizados 80 camundongos machos com idades variando entre 8 e 10 semanas, sendo 40 animais 129/Sv WT e 40 animais 129/Sv 5-LOKO, os quais foram submetidos à exodontia do dente incisivo superior direito e divididos em quatro grupos de acordo com o tratamento: Grupo WT – 0,1 ml de soro fisiológico 0,9%, Grupo WT-ZL – 0,5 mg/Kg de ácido zoledrônico (ZL), Grupo 5-LOKO - 0,1 ml de soro fisiológico 0,9%, Grupo 5-LOKO-ZL – 0,5 mg/Kg de ZL, sendo ambas soluções administradas intraperitonealmente (IP) 1x por semana até o final do experimento. Após os períodos de 7, 14 e 30 dias, cinco animais de cada grupo foram submetidos à eutanásia para remoção das maxilas direitas contendo os alvéolos para as análises histopatológica, histomorfométrica e imuno-histoquímica para COX-2, OPG, RANKL e TRAP. Os resultados não mostraram diferença significativa para a quantidade de matriz óssea entre os grupos WT, KO e WT-ZL. Contudo, foi observado que o grupo KO-ZL apresentou significativamente menos matriz óssea em todos os períodos quando comparado com WT-ZL, além de maior quantidade de células inflamatórias no 14 e 30 dias. Observou-se aumento significativo de células COX-2+ no grupo WT aos 14 dias em comparação com os demais. Detectou-se aumento de OPG ao final do reparo em todos os grupos. Aumento significativo de RANKL foi observado no grupo KO aos 7 dias, em comparação com 5-LOKO, sendo que, ao final do reparo, WT-ZL mostrou células RANKL+ significativamente elevadas em comparação com WT e KO-ZL. No entanto, somente aos 14 dias observou-se aumento significativo de células TRAP+ nos grupos WT e WT-ZL em comparação com KO e KO-ZL. A partir destes resultados, pode-se concluir que os animais 5-LOKO apresentaram formação óssea precoce em alvéolos dentários pós-exodontia comparados com os animais WT. No entanto, os efeitos do ZL foram mais deletérios nos camundongos 5-LOKO, possivelmente pela influência da droga e efeitos da inibição desta enzima nos eventos inflamatórios no curso do reparo.
Osteonecrosis of the jaws has been related to the chronic use of antiresorptive drugs indicated for diseases and disorders of bone metabolism, such as nitrogenous bisphosphonates (nBP), especially when associated with surgical-dental interventions. Thus, it is speculated that the onset of this disease does not occur only due to the condition of the bone tissue and its reactive capacity, but mainly due to its immunological defense condition. The present study aimed to analyze the bone repair pattern of dental alveoli of maxillary incisors recently extracted from 129/Sv 5-LOKO mice, which had an osteopetrotic skeletal phenotype, comparing them with wild type, 129/Sv WT, with and without administration of nBP. For that, 80 male mice were used with ages varying between 8 and 10 weeks, being 46 animals 129/Sv WT and 40 animals 129/Sv 5-LOKO, which were submitted to the extraction of the upper right incisor tooth and divided into four groups of according to treatment: WT Group - 0.1 ml of 0.9% saline solution, WT-ZL Group - 0.5 mg/Kg of zoledronic acid, Group 5-LOko - 0.1 ml of 0.9 saline solution %, Group 5-LOko-ZL – 0.5 mg/Kg of zoledronic acid, both solutions being administered intraperitoneally (IP) 1x a week until the end of the experiment. After periods of 7, 14 and 30 days, five animals from each group were euthanized to remove the right jaws containing the alveoli. They were immediately fixed in order to be prepared for the following methodological procedures: histotechnical processing for making histological slides stained with hematoxylin and eosin and immunohistochemical No significant difference was found for the amount of bone matrix between the WT, KO and WT-ZL groups. However, it was observed that the KO-ZL group presented significantly less bone matrix in all periods when compared to WT-ZL, in addition to a greater amount of inflammatory cells at 14 and 30 days. There was a significant increase in COX-2+ cells in the WT group at 14 days compared to the others. An increase in OPG was detected at the end of the repair in all groups. Significant increase in RANKL was observed in the KO group at 7 days, compared to 5-LOKO, and at the end of repair WT-ZL showed significantly elevated RANKL+ cells compared to WT and KO-ZL. However, only at 14 days there was a significant increase in TRAP+ cells in the WT and WT-ZL groups compared to KO and KO-ZL. From these results, it can be concluded that 5-LOKO animals showed early bone formation in post-extraction tooth sockets compared to WT animals. However, the effects of ZL were more deleterious in 5-LOKO mice, possibly due to the influence of the drug and the effects of inhibition of this enzyme on inflammatory events in the course of repair.
Osteonecrosis of the jaws has been related to the chronic use of antiresorptive drugs indicated for diseases and disorders of bone metabolism, such as nitrogenous bisphosphonates (nBP), especially when associated with surgical-dental interventions. Thus, it is speculated that the onset of this disease does not occur only due to the condition of the bone tissue and its reactive capacity, but mainly due to its immunological defense condition. The present study aimed to analyze the bone repair pattern of dental alveoli of maxillary incisors recently extracted from 129/Sv 5-LOKO mice, which had an osteopetrotic skeletal phenotype, comparing them with wild type, 129/Sv WT, with and without administration of nBP. For that, 80 male mice were used with ages varying between 8 and 10 weeks, being 46 animals 129/Sv WT and 40 animals 129/Sv 5-LOKO, which were submitted to the extraction of the upper right incisor tooth and divided into four groups of according to treatment: WT Group - 0.1 ml of 0.9% saline solution, WT-ZL Group - 0.5 mg/Kg of zoledronic acid, Group 5-LOko - 0.1 ml of 0.9 saline solution %, Group 5-LOko-ZL – 0.5 mg/Kg of zoledronic acid, both solutions being administered intraperitoneally (IP) 1x a week until the end of the experiment. After periods of 7, 14 and 30 days, five animals from each group were euthanized to remove the right jaws containing the alveoli. They were immediately fixed in order to be prepared for the following methodological procedures: histotechnical processing for making histological slides stained with hematoxylin and eosin and immunohistochemical No significant difference was found for the amount of bone matrix between the WT, KO and WT-ZL groups. However, it was observed that the KO-ZL group presented significantly less bone matrix in all periods when compared to WT-ZL, in addition to a greater amount of inflammatory cells at 14 and 30 days. There was a significant increase in COX-2+ cells in the WT group at 14 days compared to the others. An increase in OPG was detected at the end of the repair in all groups. Significant increase in RANKL was observed in the KO group at 7 days, compared to 5-LOKO, and at the end of repair WT-ZL showed significantly elevated RANKL+ cells compared to WT and KO-ZL. However, only at 14 days there was a significant increase in TRAP+ cells in the WT and WT-ZL groups compared to KO and KO-ZL. From these results, it can be concluded that 5-LOKO animals showed early bone formation in post-extraction tooth sockets compared to WT animals. However, the effects of ZL were more deleterious in 5-LOKO mice, possibly due to the influence of the drug and the effects of inhibition of this enzyme on inflammatory events in the course of repair.
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Palavras-chave
Difosfonatos, Camundongos, Regeneração óssea, Diphosphonates