Synergistic alveolar bone resorption by diabetic advanced glycation end products and mechanical forces

Abstract

Background The association between diabetes mellitus (DM) and bone diseases is acknowledged. However, the mechanistic pathways leading to the alveolar bone (AB) destruction remain unclear. This study aims to elucidate the mechanical forces (MF)‐induced AB destruction in DM and its underlying mechanism. Methods In vivo periodontal tissue responses to MF were evaluated in rats with diabetes. In vitro human periodontal ligament (PDL) cells were either treated with advanced glycation end products (AGEs) alone or with AGEs and MF. Results In vivo, the transcription of VEGF‐A, colony stimulating factor‐1 (CSF‐1), and Ager was upregulated in diabetes, whereas changes in DDOST and Glo1 mRNAs were negligible. DM induced VEGF‐A protein in the vascular cells of the PDL and subsequent angiogenesis, but DM itself did not induce osteoclastogenesis. MF‐induced AB resorption was augmented in DM, and such augmentation was morphologically substantiated by the occasional undermining resorption as well as the frontal resorption of the AB by osteoclasts. The mRNA levels of CSF‐1 and vascular endothelial growth factor (VEGF) during MF application were highly elevated in diabetes, compared with those of the normal counterparts. In vitro, AGEs treatment elevated Glut‐1 and CSF‐1 mRNA levels via the p38 and JNK pathways, whereas OGT and VEGF levels remained unchanged. Compressive MF especially caused upregulation of VEGF, CSF‐1, and Glut‐1 levels, and such upregulation was further enhanced by AGEs treatment. Conclusions Overloaded MF and AGEs metabolites may synergistically aggravate AB destruction by upregulating CSF‐1 and VEGF. Therefore, regulating the compressive overloading of teeth, as well as the levels of diabetic AGEs, may prove to be an effective therapeutic modality for managing DM‐induced AB destruction.

Mechanosensing by Gli1+ cells contributes to the orthodontic force‐induced bone remodelling

“…On tension side, the width of PDL increases with cell proliferation, then the new bone deposition on alveolar surface, leading the width of PDL to normal limits 23,27 . Given that hPDLSCs are obtained and cultured easily in vitro, they are widely applied in investigating the mechanism of OTM 6 . For example, hPDLSCs have the property of osteogenesis 24 .…”

“…Since OTM is an in vivo model with controlled force direction, magnitude and duration, it is an ideal model for investigating how force modulates bone remodelling. The cells in periodontal ligament (PDLCs), which contain fibroblasts, osteoblasts, cementoblasts, endothelial cells and stromal/stem cells, are the primary respondents to mechanical force and key factors to alveolar bone remodelling 5,6 . Given the human periodontal ligament stromal/stem cells (hPDLSCs) are obtained and cultured easily in vitro, they have been intensively evaluated to partly elucidate the mechanism of OTM 7,8 .…”

Pathogenic Molecular Mechanisms in Periodontitis and Peri-Implantitis: Role of Advanced Glycation End Products

“…This upregulation was also maintained in rats incubated with AGEs and was mediated by JNK and p38 signaling pathways. AGE receptor 1 (AGE-R1) silencing led to the reduction in CSF-1 and VEGF overexpression, even though the latter was not induced by AGEs as it was mainly expressed in PDL vascular cells rather than in fibroblastic cells [35].…”

“…Increased CSF-1 and VEGF production [35] Gingival tissues Anti-inflammatory effect of sRAGE [47] Wound healing assessment Anti-inflammatory effect of aminoguanidine [48] Periodontal tissues Increased IL-1 and TNF-α production [50] Dendritic cells and osteoclasts Reduction in dendritic cell migration [52] Human periodontal ligament cells and mesenchymal stem cells…”

The Cellular Choreography of Osteoblast Angiotropism in Bone Development and Homeostasis

“…Increased osteoclast activation then further implies increased bone resorption and bone destruction, thus accounting for the higher incidence of fractures, osteopenia, and osteoporosis that occur in type II diabetic patients which readily accumulate AGEs [ 105 ]. Growing evidence is enabling the recognition that there is a strong correlation between AGE accumulation and increased bone fragility [ 106 , 107 , 108 ]. However, the exact mechanism for this has not been conclusively established and requires further investigation.…”