Fibronectin Fragment-Induced Osteolysis Mediated by MMPs

MMP 介导的纤连蛋白片段诱导的骨溶解

• 批准号: 6910580
• 负责人: SUNIL D KAPILA
• 金额: $ 34.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6910580
• 关键词: cell differentiation; clinical research; collagen; collagenase; enzyme activity; enzyme induction /repression; fibronectins; fluorimetry; human tissue; laboratory mouse; mixed tissue /cell culture; molecular pathology; organ culture; osteoblasts; osteoclasts; pathologic bone resorption; periodontitis

DESCRIPTION: Although matrix metalloproteinases (MMPs) have been implicated in periodontitis, their role in altering the equilibrium between bone synthesis and degradation during periodontal breakdown has not been investigated. One component that may contribute to the induction of MMPs in periodontal disease is fibronectin (FN) fragments. FN fragments are found in chronic periodontitis and induce MMPs in periodontal ligament (PDL) cells. The mechanism by which MMPs cause bone breakdown in response to FN fragments may include their direct degradation of the collagenous matrix thereby facilitating osteoclastic bone resorption. Our preliminary data demonstrate that several FN fragments enhance osteoclastic activity that is paralleled by increases in MMP-9 and MMP-1, and inhibited by a MMP inhibitor. Additionally, we have shown that an increase in collagenolytic activity including that triggered by FN fragments attributable to MMP-1 and possibly MMP-13 is strongly correlated with the inhibition of osteoblastic phenotype in PDL cells. These data suggest that FN fragments may perpetuate periodontal disease by increasing net bone loss through induction of specific MMPs, which lead to disturbances in the osteogenic:osteolytic equilibrium. The overlying hypothesis of these studies is that specific MMPs induced by periodontal disease-associated FN fragments potentiate the disease by enhancing osteoclast activity and diminishing osteoblast differentiation. This investigation will assess the contribution of the FN fragment-MMP-osteoclast/osteoblast axis to periodontal breakdown by 1) determining the contribution of specific MMPs to osteoclastic bone resorption, 2) identifying the role of collagenolytic MMPs in inhibiting osteoblastic differentiation of PDL cells, and 3) determining the contribution of these FN fragment-induced MMPs in both cells to osteoclastic resorption and inhibition of osteoblastic differentiation of PDL cells in co-culture systems. These studies will provide a fundamental understanding of the basis for bone loss in periodontal disease and other osteolytic diseases.

产品说明：虽然基质金属蛋白酶（MMPs）已被牵连在牙周炎，其作用在改变骨合成和降解之间的平衡，在牙周破坏还没有调查。在牙周病中可能有助于诱导MMPs的一种组分是纤连蛋白（FN）片段。FN片段在慢性牙周炎中发现，并在牙周膜（PDL）细胞中诱导MMPs。MMPs对FN片段的反应导致骨破坏的机制可能包括它们直接降解胶原基质，从而促进骨细胞的骨吸收。我们的初步数据表明，几个FN片段增强骨细胞的活性，这是由MMP-9和MMP-1的增加，并抑制MMP抑制剂。此外，我们已经表明，胶原溶解活性的增加，包括由MMP-1和可能的MMP-13引起的FN片段触发的胶原溶解活性的增加，与PDL细胞中成骨细胞表型的抑制密切相关。这些数据表明，FN片段可能通过诱导特定的MMPs增加净骨丢失，从而导致成骨：溶骨性平衡紊乱，从而使牙周病永久化。这些研究的叠加假设是，牙周病相关FN片段诱导的特定MMPs通过增强破骨细胞活性和减少成骨细胞分化而增强疾病。本研究将通过以下方式评估FN片段-MMP-破骨细胞/成骨细胞轴对牙周破坏的贡献：1）确定特异性MMP对破骨细胞骨吸收的贡献，2）鉴定胶原溶解性MMP在抑制PDL细胞的成骨细胞分化中的作用，和3）确定这些FN片段的贡献-诱导两种细胞中的MMPs发生骨吸收，并抑制共培养体系中PDL细胞的成骨分化。这些研究将为牙周病和其他溶骨性疾病中骨丢失的基础提供一个基本的理解。