Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

Paula Goes; Caio Dutra; Lennart Lösser; Lorenz C Hofbauer; Martina Rauner; Sylvia Thiele

doi:10.3389/fimmu.2019.02924

Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis

Front Immunol. 2019 Dec 10:10:2924. doi: 10.3389/fimmu.2019.02924. eCollection 2019.

Authors

Paula Goes^{1

2}, Caio Dutra^{1

3}, Lennart Lösser¹, Lorenz C Hofbauer¹, Martina Rauner¹, Sylvia Thiele¹

Affiliations

¹ Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Technical University, Dresden, Germany.
² Department of Pathology and Legal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, Brazil.
³ Post-graduation Program in Morphofunctional Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Brazil.

Abstract

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-1^fl/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-1^fl/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-1^fl/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.

Keywords: Dkk-1; bone loss; inflammation; osteocyte; osteoimmunology; periodontitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alveolar Bone Loss / diagnostic imaging
Alveolar Bone Loss / etiology*
Alveolar Bone Loss / metabolism*
Alveolar Bone Loss / pathology
Animals
Biopsy
Bone Density
Disease Susceptibility
Intercellular Signaling Peptides and Proteins / deficiency*
Mice
Osteoblasts / metabolism
Osteocytes / metabolism*
Osteocytes / pathology
Periodontitis / complications*
Wnt Signaling Pathway
X-Ray Microtomography

Substances

Dkk1 protein, mouse
Intercellular Signaling Peptides and Proteins