ROLE OF OSTEOCYTE TbetaRII IN PERILACUNAR REMODELING AND BONE METASTASES

项目总结/文摘

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.