Fibronectin Fragment-Induced Osteolysis Mediated by MMPs

描述：虽然基质金属蛋白酶（MMPs）与牙周炎有关，但它们在牙周破裂时改变骨合成和降解平衡中的作用尚未被研究。在牙周病中可能导致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发现，并在牙周韧带（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，从而促进破骨细胞骨吸收。我们的初步数据表明，几个FN片段增强破骨活性，与MMP-9和MMP-1的增加平行，并被MMP抑制剂抑制。此外，我们已经证明，包括由MMP-1和可能的MMP-13引起的FN片段引发的胶原溶解活性的增加与PDL细胞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异性MMPs增加净骨质流失，从而导致成骨：溶骨平衡紊乱，从而使牙周病永久化。这些研究的主要假设是，由牙周病相关FN片段诱导的特异性MMPs通过增强破骨细胞活性和减少成骨细胞分化来增强疾病。本研究将评估FN片段- mmp -破骨细胞/成骨细胞轴对牙周破坏的贡献：1)确定特定MMPs对破骨细胞骨吸收的贡献；2)确定胶原溶解MMPs在抑制PDL细胞成骨分化中的作用。3)确定两种细胞中FN片段诱导的MMPs对共培养系统中PDL细胞破骨细胞吸收和成骨细胞分化抑制的贡献。这些研究将对牙周病和其他溶骨性疾病中骨质流失的基础有一个基本的了解。

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.