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: 7383934
• 负责人: SUNIL D KAPILA
• 金额: $ 33.7万
• 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/7383934
• 关键词: Affect; Arthritis; Biological Assay; Biological Availability; Bone Resorption; Calcium; Calvaria; Catabolism; Cell Differentiation process; Cells; Chronic; Coculture Techniques; Collagen; Comprehension; Culture Media; Data; Disease; Disease Progression; Equilibrium; Evaluation; Event; Fibronectins; Gelatinase B; In Vitro; Individual; Inflammatory; Interstitial Collagenase; Investigation; Lead; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mediating; Organ Culture Techniques; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Osteolytic; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phenotype; Population; Published Comment; Recombinants; Regulation; Role; Sum; System; Testing; Tissue Inhibitor of Metalloproteinase-1; Tissues; base; bone; bone loss; collagenase 1; collagenase 3; insight; novel; prevent; response

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（MMP）与牙周炎有关，但尚未研究它们在改变牙周衰竭期间骨骼合成和降解之间平衡的作用。可能有助于牙周疾病中MMP诱导的一种成分是纤连蛋白（FN）片段。 FN碎片在慢性牙周炎中发现，并在牙周韧带（PDL）细胞中诱导MMP。 MMP响应FN片段引起骨骼崩溃的机制可能包括它们直接降解胶原基质，从而促进整骨碎屑骨吸收。我们的初步数据表明，几个FN片段增强了由MMP-9和MMP-1增加并与MMP抑制剂抑制的破骨活性。此外，我们已经表明，胶原式活性的增加，包括归因于MMP-1的FN片段和MMP-13触发的胶原性活性与PDL细胞中成骨细胞表型的抑制密切相关。这些数据表明，FN片段可以通过诱导特定的MMP来增加净骨质流失来使牙周疾病永存，从而导致成骨的干扰：溶性平衡。这些研究的上覆的假设是，与牙周疾病相关的FN片段诱导的特定MMP通过增强破骨细胞活性并减少成骨细胞分化，从而增强了疾病。这项研究将评估FN碎片-MMP-MP-稳定性细胞/成骨细胞轴对牙周分解的贡献，通过1）确定特定MMP对成骨碎屑骨吸收的贡献，2）确定胶原式MMP在抑制pd oste oste的贡献中的作用，并确定了pD剂量的贡献，并确定了构成量的pd剂量 - 构成了3）的贡献。细胞在共培养系统中对PDL细胞的成骨细胞分化的骨质吸收和抑制。这些研究将提供对牙周疾病和其他溶骨疾病的骨质流失基础的基本理解。