Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis
Background: Periodontitis is a highly prevalent infection-triggered inflammatory disease that results in bone loss. Inflammation causes bone resorption by osteoclasts, and also by suppression of bone formation via increase of Dickkopf-1 (Dkk-1), an inhibitor of Wnt signaling. Here, we tested the hyp...
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doaj-27e8cecfc02747a29155e2af4adcf3802020-11-25T00:53:44ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-12-011010.3389/fimmu.2019.02924487541Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With PeriodontitisPaula Goes0Paula Goes1Caio Dutra2Caio Dutra3Lennart Lösser4Lorenz C. Hofbauer5Martina Rauner6Sylvia Thiele7Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, GermanyDepartment of Pathology and Legal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, BrazilDivision of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, GermanyPost-graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, BrazilDivision of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, GermanyDivision of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, GermanyDivision of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, GermanyDivision of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, GermanyBackground: Periodontitis is a highly prevalent infection-triggered inflammatory disease that results in bone loss. Inflammation causes bone resorption by osteoclasts, and also by suppression of bone formation via increase of Dickkopf-1 (Dkk-1), an inhibitor of Wnt signaling. Here, we tested the hypothesis that osteocytic Dkk-1 is a key factor in the pathogenesis of periodontitis-induced alveolar bone loss (ABL).Methods: Twelve-week-old female mice with a constitutive deletion of Dkk-1 specifically in osteocytes (Dkk-1fl/fl;Dmp1:Cre) were subjected to experimental periodontitis (EP). Cre-negative littermates served as controls. EP was induced by placing a ligature around the upper 2nd left molar, the contralateral side was used as control. Mice were killed after 11 days and maxillae removed for micro-CT and histological analyses. The mRNA expression of Dkk-1, Runx2, Osteocalcin, OPG, RANKL, RANKL/OPG ratio, LEF-1, and TCF-7 were assessed in maxillae, while mRNA expressions of TNF and IL-1 were evaluated on gingiva using real-time PCR. Blood samples were collected for Dkk-1, CTX, and P1NP measurement by ELISA.Results: The deletion of Dkk-1 in osteocytes prevented ABL in mice with EP, compared to Cre-negative control mice with EP. Micro-CT analysis showed a significant reduction of bone loss (−28.5%) in EP Dkk-1fl/fl;Dmp1:Cre-positive mice compared to their littermate controls. These mice showed a greater alveolar bone volume, bone mineral density, trabecular number, and trabecular thickness after EP when compared to the Cre-negative controls. The local expression in maxillae as well as the serum levels of Dkk-1 were reduced in Dkk-1fl/fl;Dmp1:Cre-positive mice with EP. The transgenic mice submitted to EP showed increase of P1NP and reduction of CTX-I serum levels, and increase of TCF-7 expression. Histological analysis displayed less inflammatory infiltrates, a reduction of TNF and IL-1 expressions in the gingiva and fewer osteoclasts in Cre-positive animals with EP. Moreover, in mice with EP, the osteocytic deletion of Dkk-1 enhanced bone formation due to increased expressions of Runx2 and Osteocalcin and decreased expression of RANKL in maxillae.Conclusion: In summary, Dkk-1 derived from osteocytes plays a crucial role in ABL in periodontitis.https://www.frontiersin.org/article/10.3389/fimmu.2019.02924/fullperiodontitisDkk-1osteocyteinflammationbone lossosteoimmunology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paula Goes Paula Goes Caio Dutra Caio Dutra Lennart Lösser Lorenz C. Hofbauer Martina Rauner Sylvia Thiele |
spellingShingle |
Paula Goes Paula Goes Caio Dutra Caio Dutra Lennart Lösser Lorenz C. Hofbauer Martina Rauner Sylvia Thiele Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis Frontiers in Immunology periodontitis Dkk-1 osteocyte inflammation bone loss osteoimmunology |
author_facet |
Paula Goes Paula Goes Caio Dutra Caio Dutra Lennart Lösser Lorenz C. Hofbauer Martina Rauner Sylvia Thiele |
author_sort |
Paula Goes |
title |
Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis |
title_short |
Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis |
title_full |
Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis |
title_fullStr |
Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis |
title_full_unstemmed |
Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis |
title_sort |
loss of dkk-1 in osteocytes mitigates alveolar bone loss in mice with periodontitis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2019-12-01 |
description |
Background: Periodontitis is a highly prevalent infection-triggered inflammatory disease that results in bone loss. Inflammation causes bone resorption by osteoclasts, and also by suppression of bone formation via increase of Dickkopf-1 (Dkk-1), an inhibitor of Wnt signaling. Here, we tested the hypothesis that osteocytic Dkk-1 is a key factor in the pathogenesis of periodontitis-induced alveolar bone loss (ABL).Methods: Twelve-week-old female mice with a constitutive deletion of Dkk-1 specifically in osteocytes (Dkk-1fl/fl;Dmp1:Cre) were subjected to experimental periodontitis (EP). Cre-negative littermates served as controls. EP was induced by placing a ligature around the upper 2nd left molar, the contralateral side was used as control. Mice were killed after 11 days and maxillae removed for micro-CT and histological analyses. The mRNA expression of Dkk-1, Runx2, Osteocalcin, OPG, RANKL, RANKL/OPG ratio, LEF-1, and TCF-7 were assessed in maxillae, while mRNA expressions of TNF and IL-1 were evaluated on gingiva using real-time PCR. Blood samples were collected for Dkk-1, CTX, and P1NP measurement by ELISA.Results: The deletion of Dkk-1 in osteocytes prevented ABL in mice with EP, compared to Cre-negative control mice with EP. Micro-CT analysis showed a significant reduction of bone loss (−28.5%) in EP Dkk-1fl/fl;Dmp1:Cre-positive mice compared to their littermate controls. These mice showed a greater alveolar bone volume, bone mineral density, trabecular number, and trabecular thickness after EP when compared to the Cre-negative controls. The local expression in maxillae as well as the serum levels of Dkk-1 were reduced in Dkk-1fl/fl;Dmp1:Cre-positive mice with EP. The transgenic mice submitted to EP showed increase of P1NP and reduction of CTX-I serum levels, and increase of TCF-7 expression. Histological analysis displayed less inflammatory infiltrates, a reduction of TNF and IL-1 expressions in the gingiva and fewer osteoclasts in Cre-positive animals with EP. Moreover, in mice with EP, the osteocytic deletion of Dkk-1 enhanced bone formation due to increased expressions of Runx2 and Osteocalcin and decreased expression of RANKL in maxillae.Conclusion: In summary, Dkk-1 derived from osteocytes plays a crucial role in ABL in periodontitis. |
topic |
periodontitis Dkk-1 osteocyte inflammation bone loss osteoimmunology |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.02924/full |
work_keys_str_mv |
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