RESUMO
Bacterial pathogens stimulate periodontitis, the most common osteolytic disease in humans and the most common cause of tooth loss in adults. Previous studies identified leukocytes and their products as key factors in this process. We demonstrate for the first time that osteoblast lineage cells play a critical role in periodontal disease. Oral infection stimulated nuclear localization of NF-κB in osteoblasts and osteocytes in the periodontium of wild type but not transgenic mice that expressed a lineage specific dominant negative mutant of IKK (IKK-DN) in osteoblast lineage cells. Wild-type mice were also susceptible to bacteria induced periodontal bone loss but transgenic mice were not. The lack of bone loss in the experimental group was linked to reduced RANKL expression by osteoblast lineage cells that led to diminished osteoclast mediated bone resorption and greater coupled new bone formation. The results demonstrate that osteoblast lineage cells are key contributors to periodontal bone loss through an NF-κB mediated mechanism.
Assuntos
Perda do Osso Alveolar/metabolismo , Linhagem da Célula , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/etiologia , Animais , Biomarcadores , Densidade Óssea , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/antagonistas & inibidores , Osteocalcina/metabolismo , Osteoclastos/metabolismo , Osteogênese , Periodontite/etiologia , Periodontite/metabolismo , Transporte Proteico , Ligante RANK/metabolismo , RadiografiaRESUMO
Re-epithelialization is an important part in mucosal wound healing. Surprisingly little is known about the impact of diabetes on the molecular events of mucosal healing. We examined the role of the transcription factor forkhead box O1 (Foxo1) in oral wounds of diabetic and normoglycemic mice with keratinocyte-specific Foxo1 deletion. Diabetic mucosal wounds had significantly delayed healing with reduced cell migration and proliferation. Foxo1 deletion rescued the negative impact of diabetes on healing but had the opposite effect in normoglycemic mice. Diabetes in vivo and in high glucose conditions in vitro enhanced expression of chemokine (C-C motif) ligand 20 (CCL20) and interleukin-36γ (IL-36γ) in a Foxo1-dependent manner. High glucose-stimulated Foxo1 binding to CCL20 and IL-36γ promoters and CCL20 and IL-36γ significantly inhibited migration of these cells in high glucose conditions. In normal healing, Foxo1 was needed for transforming growth factor-ß1 (TGF-ß1) expression, and in standard glucose conditions, TGF-ß1 rescued the negative effect of Foxo1 silencing on migration in vitro. We propose that Foxo1 under diabetic or high glucose conditions impairs healing by promoting high levels of CCL20 and IL-36γ expression but under normal conditions, enhances it by inducing TGF-ß1. This finding provides mechanistic insight into how Foxo1 mediates the impact of diabetes on mucosal wound healing.