Osteoblast stimulation effects on osteoclast activity

描述(申请人提供)：这项研究的长期目标是阐明种植体诱导骨溶解的机制以及机械负荷对这一过程的影响(S)。本申请中提出的生物培训加上申请者的工程背景，将使申请者能够完成这里提出的研究，并发展未来针对骨溶解的研究。目前应用的目标是确定底物在增强成骨细胞的机械反应中的作用以及刺激的可溶性因子对破骨细胞的影响。具体地说，我们将通过分析人工和天然基质上有通讯能力和缺乏通讯能力的成骨细胞系中的这些因素，来确定基质是否有助于细胞扁平化、细胞网络和细胞间通讯。然后，我们将通过量化流体诱导细胞分泌的骨保护素(OPG)及其配体(RANKL)水平来确定这些因素是否对成骨细胞的机械反应起作用。最后，我们将通过量化破骨细胞在成骨细胞流体流动研究中存在和不存在刺激介质的情况下破骨细胞的OPG、RANKL和骨吸收来确定增强的成骨细胞反应性是否与抑制破骨细胞生成和功能性破骨细胞活动有关。我们认为，相对于人工底物，天然底物通过促进细胞扁平化、细胞联网和细胞间通讯来促进成骨细胞的机械反应。此外，我们认为成骨细胞和破骨细胞之间存在偶联机制，能够协调骨形成和骨吸收，并且成骨细胞活性的刺激导致促进抑制破骨细胞生成和破骨细胞活性的可溶性因子的上调。未来的工作将集中在发展包含骨基质的原位机械转导模型。这一领域的研究将阐明正常细胞感知和响应机械负荷的机制，以及环境在这一过程中的影响。这是了解与疾病和负荷环境改变相关的这些机制崩溃的第一步。这项工作有几个临床相关的应用，包括种植和转移诱导的骨溶解，骨质疏松，骨化生，骨折愈合和功能组织工程。

DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate the mechanisms involved in implant-induced osteolysis and the effect(s) of mechanical loading on this process. Biological training proposed in this application augmented with the applicant's engineering background, would enable the applicant to complete the research proposed herein and develop future research aimed at osteolysis. The goal of the current application is to determine the role of the substrate in enhancing the mechanoresponsiveness of osteoblastic cells and the effects of stimulated soluble factors on osteoclastic cells. Specifically, we will determine if substrate contributes to cell flattening, cell networking and cell-cell communication by analyzing these factors in communication-competent and -deficient osteoblastic cell lines on artificial and native substrates. We will then determine if these factors contribute to the mechanoresponsiveness of osteoblastic cells by quantifying fluid flow-induced cell secreted levels of osteoprotegerin (OPG) and its ligand (RANKL). Finally, we will determine if enhanced osteoblastic responsiveness is coupled to an inhibition of osteoclastogenesis and functional osteoclastic activity by quantifying OPG, RANKL and bone resorption by osteoclasts in the presence and absence of stimulated media from the osteoblastic fluid flow studies. We propose that a native substrate, relative to an artificial substrate, contributes to the mechanoresponsiveness of osteoblastic cells by promoting cell flattening, cell networking and cell-cell communication. Furthermore, we propose that coupling mechanisms exist between osteoblastic and osteoclastic cells which enable the orchestration of bone formation and resorption and that stimulation of osteoblastic activity results in an upregulation of soluble factors promoting inhibition of osteoclastogenesis and osteoclastic activity. Future work will focus on the development of in situ mechanotransduction models incorporating bone substrates. Research in this area will illuminate the mechanisms by which normal cells sense and respond to mechanical loading and the effects of the milieu in this process. This is the first step in understanding the breakdown of these mechanisms associated with disease and altered loading environments. This work has several clinically relevant applications including implant- and metastatic-induced osteolysis, osteoporosis, osteopetrosis, fracture healing and functional tissue engineering.