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.

描述：尽管基质金属蛋白酶(MMPs)与牙周炎有关，但它们在牙周破裂过程中改变骨合成和降解之间的平衡的作用尚未被研究。可能在牙周病中诱导MMPs的一个成分是纤维连接蛋白(FN)片段。FN片段在慢性牙周炎中广泛存在，可诱导牙周膜(PDL)细胞产生MMPs。MMPs对FN片段的反应导致骨质破坏的机制可能包括它们直接降解胶原基质，从而促进破骨细胞性骨吸收。我们的初步数据表明，几个FN片段增强了破骨细胞的活性，这与基质金属蛋白酶-9和基质金属蛋白酶-1的增加是平行的，并被基质金属蛋白酶抑制剂抑制。此外，我们还发现，胶原溶解活性的增加，包括由可归因于基质金属蛋白酶-1和可能的基质金属蛋白酶-13的FN片段所触发的活性，与抑制PDL细胞的成骨细胞表型密切相关。这些数据表明，FN片段可能通过诱导特定的MMPs而增加净骨丢失，从而导致成骨：骨溶解平衡的紊乱，从而使牙周疾病永久化。这些研究的基本假设是，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加重疾病。本研究将通过1)确定特定的MMPs在破骨细胞性骨吸收中的作用，2)确定胶原溶解MMPs在抑制PDL细胞成骨分化中的作用，以及3)在共培养体系中确定FN片段诱导的这些MMPs在两种细胞中对破骨细胞吸收和抑制PDL细胞成骨分化的作用，来评估FN片段-MMP-破骨细胞/成骨细胞轴在牙周破坏中的作用。这些研究将对牙周病和其他溶骨性疾病中骨丢失的基础有一个基本的了解。