ROLE OF OSTEOCYTE TbetaRII IN PERILACUNAR REMODELING AND BONE METASTASES

骨细胞 TbetaRII 在腔周重塑和骨转移中的作用

• 批准号: 9190982
• 负责人: Tristan William Fowler
• 金额: $ 1.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2016-10-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190982
• 关键词: Address; Affect; Binding Proteins; Biochemical; Bone Matrix; Bone Resorption; Bone neoplasms; Bone remodeling; Cancer Biology; Cells; Chemicals; Collagen; Cues; Data; Defect; Development; Enzymes; Equilibrium; Family; Foundations; Fracture; Goals; Growth; Growth Factor Gene; Health; Homeostasis; Institution; Investigation; Knock-out; Maintenance; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mechanics; Mediating; Metastatic Neoplasm to the Bone; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Organ; Osteoblasts; Osteoclasts; Osteocytes; Outcome; Paracrine Communication; Pathway interactions; Process; Regulation; Research; Risk; Role; Signal Transduction; Skeleton; Solid; Stimulus; Stretching; Structure; Testing; Tissues; Training; Transforming Growth Factor beta; Tumor Burden; abstracting; bone; bone cell; bone health; bone mass; bone quality; cancer complication; cancer site; career; cell growth; cell type; in vivo; insight; mineralization; mouse model; neoplastic cell; novel; prostate cancer cell; quantitative imaging; receptor; response; skeletal; skills; tumor

PROJECT SUMMARY/ABSTRACT The skeleton is a dynamic and responsive tissue that all other organs use for stability and structure. To maintain the integrity of skeleton, bone cells are constantly involved in the organized destruction and rebuilding of the bone matrix, a process known as bone remodeling. While much is known about the activity of the bone forming osteoblasts and the bone degrading osteoclasts, the cell that has been shown to be the central regulator of bone remodeling, the osteocyte, has received less consideration. Osteocytes reside inside the bone matrix, are the most abundant cell in the skeleton, and are connected through an intricate network of canalicular processes stretching throughout the bone. This network allows osteocytes to respond to mechanical stimuli such as load, or chemical stimuli such as growth factors. In response to these stimuli, osteocytes remodel their adjacent matrix in a process known as perilacunar remodeling (PLR). Transforming growth factor-beta (TGFβ), one of the most prominently studied growth factors in bone, has been shown to regulate many processes in bone cells by signaling through the type-II TGFβ receptor (TβRII). However, the exact function of TβRII in osteocyte driven PLR remains unknown. Furthermore, when bone matrix is exposed during remodeling, stored active-TGFβ is liberated and therefore the local concentration of this potent growth factor increased. The exposed matrix, with binding proteins and growth factors readily available, has proven to be an attractive site for cancer to metastasize and develop tumors. This leads to the release of more growth factor and repeats in a vicious cycle of bone degradation, tumor development, and ultimately increased fracture and morbidity. Therefore, this project tests the hypothesis that TβRII dependent signaling controls PLR, and further, that osteocytes regulate bone metastasis progression through a TGFβ dependent pathway. A focused, three-year investigation is proposed to determine the cellular and molecular mechanisms behind TGFβ control of osteocyte activity in healthy bone and in the case of prostate cancer bone metastasis. In the first Aim, I will produce a mouse model with an osteocyte specific knockout of TβRII and determine the effect this has on outcomes of PLR. In the second Aim, I will assess the bone tumor burden after inoculation of the mouse model with prostate cancer cells. This approach will provide insight into how TGFβ signaling controls PLR and identify new mechanisms controlling the vicious cycle of cancer bone metastasis.

项目总结/摘要 骨骼是一个动态和反应性的组织，所有其他器官都使用它来保持稳定和结构。 为了维持骨骼的完整性，骨细胞不断参与有组织的破坏 以及骨基质的重建，这一过程被称为骨重建。虽然我们知道很多关于 骨形成成骨细胞和骨降解破骨细胞的活性， 被证明是骨重建的中心调节器，骨细胞， 考虑.骨细胞位于骨基质内，是骨骼中最丰富的细胞， 并通过一个错综复杂的网络连接的小管过程中伸展整个 骨头该网络允许骨细胞对机械刺激如负荷或化学刺激作出反应。 刺激物，如生长因子。骨细胞对这些刺激的反应是重塑其邻近的基质 这一过程被称为半月板周围重塑（PLR）。转化生长因子β（TGFβ）， 骨中最突出的研究生长因子，已被证明可以调节许多过程， 通过II型TGFβ受体（TβRII）信号传导骨细胞。然而， TβRII在骨细胞驱动的PLR中的作用尚不清楚。此外，当骨基质暴露于 重塑，储存的活性TGF β被释放，因此这种有效生长的局部浓度 因素增加。暴露的基质，结合蛋白和生长因子容易获得， 被证明是癌症转移和发展肿瘤的一个有吸引力的部位。这导致 释放更多的生长因子，并重复骨降解，肿瘤发展， 并最终增加骨折和发病率。因此，本项目测试的假设， TβRII依赖性信号传导控制PLR，进而骨细胞调节骨转移 通过TGFβ依赖性途径进展。建议进行为期三年的重点调查， 确定TGFβ控制健康人骨细胞活性的细胞和分子机制， 在前列腺癌骨转移的情况下。在第一个目标中，我将产生一只老鼠 模型与骨细胞特异性敲除TβRII，并确定这对结果的影响 PLR。在第二个目标中，我将评估小鼠模型接种后的骨肿瘤负荷 与前列腺癌细胞。这种方法将提供深入了解TGFβ信号转导如何控制PLR 并确定控制癌症骨转移恶性循环的新机制。