Oral Mucosa in Bisphosphonate-associated Osteonecrosis of the Jaw

双膦酸盐相关颌骨坏死的口腔粘膜

• 批准号: 7938866
• 负责人: Kotaro Sena
• 金额: $ 7.43万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938866
• 关键词: Acids; Affect; Angiogenic Factor; Award; Biological Assay; Bone necrosis; Cancer Patient; Cells; Clinical; Dental Implants; Dentures; Development; Dose; Event; Exostoses; Failure; Fibroblast Growth Factor 2; Functional disorder; Funding Opportunities; Gene Expression; Genes; Healed; Histology; Hypoxia; Immunofluorescence Immunologic; Implantation procedure; In Vitro; Individual; Intravenous; Jaw; Knowledge; Lead; Lesion; Life; Malignant Neoplasms; Mandible; Maxilla; Methods; Modeling; Molecular Mechanisms of Action; Morbidity - disease rate; Oral; Oral cavity; Oral mucous membrane structure; Osteoporosis; Pathogenesis; Patients; Periodontal Diseases; Platelet-Derived Growth Factor; Primary Lesion; Process; Production; Quality of life; Rattus; Reporting; Research; Research Project Grants; Risk; Staging; Symptoms; Testing; Tooth Extraction; Vascular Endothelial Growth Factor A; Wound Healing; Zoledronic Acid; alveolar bone; angiogenesis; bisphosphonate; bone; bone turnover; career; cytotoxic; healing; in vivo; intravenous administration; meetings; pamidronate; public health relevance; real time model; reconstitution; research study; response; soft tissue

DESCRIPTION (provided by applicant): Bisphosphonate-associated osteonecrosis of the jaw (ONJ) adversely affects the quality of life and produces significant morbidity in afflicted patients. It is characterized by the finding of exposed alveolar bone in the oral cavity. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates (Pamidronate and Zolendronic acid) is higher, ranging from 1 to 10 %, compared to patients with osteoporosis treated with low dose, oral bisphosphonates (0.00001 to 0.0001 %). It has been assumed that the primary lesion for ONJ lies in bone and is related to over-suppression of bone turnover. However, it is unclear why these lesions present with loss of the oral mucosal covering of the mandible or maxilla as the primary clinical feature. A possible explanation of this symptom is that bisphosphonates are accumulated in bone in concentrations sufficient to be directly toxic to the oral mucosa and result in the failure of healing of soft tissue lesions, leading to the pathogenesis of ONJ. In addition, tooth extraction is the dominating event preceding ONJ, although other causes such as periodontal disease, dental implant procedures, exostoses, and ill-fitting dentures are also preceding factors for ONJ. Moreover, an anti-angiogenic effect of bisphosphonates has been reported recently. Since sufficient reconstitution of vasculature is prerequisite for wound healing, suppression of angiogenesis may result in the failure of healing of soft tissue lesions leading to the pathogenesis of ONJ. Although, these findings suggest involvement of bisphosphonate on oral mucosa in the development and/or progression ONJ, the effect of intravenous bisphosphonates on oral mucosa has not been studied in vivo. Our overall hypothesis is that intravenous bisphosphonates may inhibit healing of oral mucosa and contribute to the development and/or progression ONJ. We plan to elucidate the relationship between bisphosponates and the oral mucosa by testing the following Aims. In Aim 1, we will determine the cytotoxic effect of intravenous bisphosphonate, zoledronic acid, on oral mucosa, in vivo, during the wound healing process after tooth extraction in a rat model, by utilizing basic histology and the live/dead cell vitality assay. The aim will demonstrate the cytotoxic effect of zoledronic acid during healing of oral mucosa after tooth extraction. In Aim 2.1, we will determine if reconstitution of the vasculature in the oral mucosa is altered by zoledronic acid during the healing process after a tooth extraction, using immunofluorescence method. In Aim 2.2 we will further investigate whether the alternation of vasculature reconstitution is due to suppression of angiogenic and hypoxia related gene expression. The aim will demonstrate the anti-angiogenic effect of zoledronic acid during healing of oral mucosa after tooth extraction, in vivo. If successful, the proposed experiments will advance research that will fill a current knowledge gap in characterization of molecular mechanisms of action of intravenous bisphosphonates on oral soft tissues that may subsequently lead to the understanding of pathophysiology of development and/or progression of bisphosphonate-associated ONJ. PUBLIC HEALTH RELEVANCE: Bisphosphonate-associated osteonecrosis of the jaw (ONJ) is characterized by the finding of exposed alveolar bone in the oral cavity and adversely affects the quality of life and produces significant morbidity in afflicted patients. The underlying pathogenesis of ONJ is yet to be clearly elucidated. The proposed experiments will advance research that will fill a current knowledge gap in characterization of molecular mechanisms of action of intravenous bisphosphonates on oral soft tissues that subsequently lead to the understanding of pathophysiology of development and/or progression of bisphosphonate-associated ONJ.

描述（由申请方提供）：双膦酸盐相关性颌骨骨坏死（ONJ）对患者的生活质量产生不利影响，并导致患者严重发病。其特征在于在口腔中发现暴露的牙槽骨。与接受低剂量口服双膦酸盐治疗的骨质疏松症患者（0.00001 - 0.0001%）相比，接受高剂量静脉双膦酸盐（帕米膦酸盐和唑来膦酸）治疗的癌症患者发生ONJ的风险更高，范围为1%-10%。据推测，ONJ的原发性病变位于骨中，并与骨转换的过度抑制有关。然而，目前尚不清楚为什么这些病变的主要临床特征是下颌骨或上颌骨的口腔粘膜覆盖丧失。这种症状的一种可能解释是，二膦酸盐在骨中蓄积的浓度足以对口腔粘膜直接产生毒性，导致软组织病变愈合失败，从而导致ONJ的发病机制。此外，拔牙是ONJ之前的主要事件，尽管其他原因，如牙周病，牙科种植手术，外生骨疣和不合适的假牙也是ONJ的前因。此外，最近已经报道了双膦酸盐的抗血管生成作用。由于血管系统的充分重建是伤口愈合的先决条件，抑制血管生成可能导致软组织病变愈合失败，从而导致ONJ的发病机制。尽管这些发现表明，双膦酸盐对口腔粘膜的影响与ONJ的发生和/或进展有关，但尚未在体内研究静脉内双膦酸盐对口腔粘膜的影响。我们的总体假设是，静脉注射双膦酸盐可能会抑制口腔粘膜的愈合，并有助于ONJ的发展和/或进展。我们计划通过测试以下目标来阐明双膦酸盐与口腔粘膜之间的关系。在目的1中，我们将通过利用基本组织学和活/死细胞活力测定，在大鼠模型拔牙后伤口愈合过程中，确定静脉注射双膦酸盐（唑来膦酸）对口腔粘膜的体内细胞毒性作用。目的是证明拔牙后口腔粘膜愈合过程中唑来膦酸的细胞毒性作用。在目标2.1中，我们将使用免疫荧光方法确定拔牙后愈合过程中唑来膦酸是否改变口腔粘膜血管重建。在目的2.2中，我们将进一步研究血管重建的改变是否是由于血管生成和缺氧相关基因表达的抑制。目的是证明唑来膦酸在拔牙后口腔粘膜愈合过程中的体内抗血管生成作用。如果成功，拟议的实验将推进研究，填补目前在表征静脉内双膦酸盐对口腔软组织作用的分子机制方面的知识空白，随后可能导致对双膦酸盐相关ONJ发展和/或进展的病理生理学的理解。 公共卫生相关性：双膦酸盐相关性颌骨骨坏死（ONJ）的特征在于在口腔中发现暴露的牙槽骨，并且对患者的生活质量产生不利影响，并且在患病患者中产生显著的发病率。ONJ的潜在发病机制尚未明确阐明。拟议的实验将推进研究，填补目前在表征静脉内双膦酸盐对口腔软组织作用的分子机制方面的知识空白，从而了解双膦酸盐相关ONJ的发展和/或进展的病理生理学。