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

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.

Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus

“…However, Cre+ mice were largely protected from this effect. Interestingly, serum CTX did not reflect the histological increase in osteoclast numbers, similar to our findings in healthy Dkk1-deficient mice, suggesting that Dkk1 rather affects osteoclast numbers than osteoclast activity 23 , 54 . Inhibition of Dkk1 has already been associated with suppressed bone resorption.…”

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

“…On the other hand, in osteocyte-specific Dkk1-deficient mice, the expression of TCF-7 remained at the control level, and the expression of LEF-1 was not changed compared to WT mice. In this study, Dkk-1 derived from osteocytes played a crucial role in alveolar bone loss in periodontitis [69].…”

Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases

“…Stimulated macrophages, DCs, and T cells promote the expression level of RANKL in periodontal ligament cells and osteoblasts through their corresponding pro-inflammatory cytokines so as to initiate bone resorption performed by osteoclasts, with OPG being degraded as well (Tsukasaki, 2020), resulting in reduced RANKL/OPG ratio, which leads to alveolar bone lesion even tooth loss. Nowadays, there are more and more advanced researches focusing on the potential key molecule or signaling pathway targeted at regulating osteoimmune microenvironment in periodontitis (Goes et al, 2019;Li et al, 2020;, which may provide novel perspectives and contribute to the therapeutic approaches for periodontitis based on osteoimmunomodulation. For instance, in a recent study, Wu et al (2020) revealed the new AKT2/c-Jun N-terminal kinase (JNK)1/2/c-jun and AKT2/miR-155-5p/DET1/c-Jun signaling pathways that played a role in altering macrophage polarization and regulating periodontitis inflammation and AKT2 promoted M2 polarization of macrophages, suggesting a novel strategy for periodontitis treatment.…”