Osteocyte Integrity and Bone Remodeling

骨细胞完整性和骨重塑

• 批准号: 8034807
• 负责人: MITCHELL B SCHAFFLER
• 金额: $ 32.2万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034807
• 关键词: Aging; Apoptosis; Apoptotic; Area; Behavior; Bone Resorption; Bone Tissue; Bone remodeling; Caspase Inhibitor; Cell Death; Cell Line; Cells; Cessation of life; Cytokine Signaling; Data; Estrogens; Excision; Exhibits; Fatigue; Funding; Goals; Gonadal Steroid Hormones; Grant; Health; Immobilization; Immunohistochemistry; In Vitro; Individual; Inhibition of Apoptosis; Investigation; Label; Lead; Life; Link; Macrophage Colony-Stimulating Factor; Measures; Mechanics; Mediator of activation protein; Metabolic; Microscopic; Modeling; Osteoblasts; Osteoclasts; Osteocytes; Osteoporosis; Ovariectomy; Pathway interactions; Pattern; Phagocytes; Play; Postmenopausal Osteoporosis; Principal Investigator; Process; Production; Rattus; Relative (related person); Role; Series; Signal Transduction; Site; Source; Spatial Distribution; Stimulus; TNFSF11 gene; Testing; Time; Tissues; Vascular Endothelial Growth Factors; Withdrawal; attenuation; base; bone; bone disuse atrophy; bone loss; bone quality; clinically relevant; in vivo; in vivo Model; insight; mouse model; new therapeutic target; novel; osteoclastogenesis; prevent; programs; release factor; response

DESCRIPTION (provided by applicant): Turnover of cells and matrix in bone occur through osteonal remodeling, wherein resorption removes and osteoblastic infilling replaces microscopic regions of compact bone that have reached the end of their functional life. Imbalances in this turnover process can lead to impaired bone quality and increased fragility. How bone remodeling targets area of bone has long been unclear. We found that inhibiting osteocyte apoptosis after fatigue prevents activation of osteoclastic resorption, demonstrating for the first time that osteocyte apoptosis is a controlling step in the activation of targeted bone resorption of microdamage. We also discovered that the spatial and temporal relationships between osteocyte apoptosis and osteoclastic bone resorption previously established for remodeling of microdamage in bone hold as well for resorption induced by ovariectomy and disuse. Finally, we found that the surviving osteocytes near areas of microdamage also appear to respond to the focal microinury and may potentially secrete regulatory factors that help coordinate the osteoclastic response. In the current studies, we will use a combination of real-time PCR, immunohistochemical and histomorphometry approaches in the rat ulnar fatigue model in vivo to determine the regulatory processes by which apoptotic and non-apoptotic osteocytes surrounding microdamage signal to osteoclasts and activate bone remodeling. We will also determine which among the osteocyte derived signals is dependent upon osteocyte apoptosis by using a pan-caspase inhibitor to suppress the apoptosis. We will focus on osteocyte expression of major regulators of bone resorption that are a) an established requirements for osteoclastic differentiation and b) have demonstrated expression by, or effects on, osteocytes. Complementary in vitro studies on osteocyte-like cells will be used to test causal relationships using specific blocking approaches to determine roles of individual signaling cytokines within the pathway linking apoptotic and pro-osteoclastogenic cells. In the second series of studies, we will use the rat ulnar fatigue model to establish the importance of osteocyte apoptosis in the activation versus progression of bone resorption around microdamage. Finally, we will test whether osteocyte apoptosis is a 'common final pathway' for initiation of bone resorption in response to diverse remodeling stimuli, by using a pan-caspase inhibitor to suppress osteocyte apoptosis in mouse models for estrogen withdrawal and disuse. PUBLIC HEALTH RELEVANCE. Maintaining bone quality and preventing bone tissue fragility depends upon bone remodeling, wherein osteoclasts remove and osteoblasts replace microscopic regions of bone that have reached the end of their functional life. Our recent discoveries indicate that this remodeling, as well as the increased turnover and bone loss in postmenopausal and disuse osteoporoses, in turn, depends of the regulated death (apoptosis) of osteocytes within the bone. These findings suggest that osteocyte apoptosis may be a 'common final pathway' controlling bone resorption in response to diverse remodeling stimuli, and also suggest that this apoptosis could represent a novel therapeutic target for modulating osteoclastic activity in aging and osteoporosis.

描述（由申请人提供）：骨骼中细胞和基质的营业额通过骨重塑发生，其中吸收去除和成骨细胞填充替代了已达到其功能寿命的紧凑骨的微观区域。在此周转过程中的失衡会导致骨质质量受损和脆弱性增加。长期以来，骨骼重塑靶标的区域如何尚不清楚。我们发现，疲劳后抑制骨细胞凋亡可防止破骨碎屑吸收的激活，这首次证明骨细胞凋亡是激活靶向骨的微塑料的控制步骤。我们还发现，以前建立的骨细胞凋亡与破骨细胞骨吸收之间的空间关系和时间关系是用于重塑骨骼中的微塑料的，以及用于卵巢切除术和废弃的吸收。最后，我们发现，在微型塑料区域附近存活的骨细胞似乎也对局灶性微观有反应，并且可能有助于分泌有助于协调破骨细胞反应的调节因素。在当前的研究中，我们将在大鼠尺尺疲劳模型中使用实时PCR，免疫组织化学和组织形态计量方法的组合来确定调节过程，通过这些调节过程，通过这些过程，凋亡和非凋亡骨细胞周围的微型骨质骨化细胞围绕微型信号信号，从而向骨化细胞骨化骨骼和活化的骨骼重塑。我们还将通过使用pan-caspase抑制剂抑制细胞凋亡，确定骨细胞衍生的信号中的哪个取决于骨细胞的凋亡。我们将重点关注骨吸收主要调节剂的骨细胞表达，这是a）对骨细胞分化的既定要求，而b）通过对骨细胞的表达或影响。对骨细胞样细胞的互补体外研究将使用特定的阻断方法来测试因果关系，以确定与凋亡和核骨构成细胞联系起来的单个信号传导细胞因子在途径中的作用。在第二系列研究中，我们将使用大鼠尺尺疲劳模型来确定骨细胞凋亡在微塑料周围骨吸收与骨吸收进展中的重要性。最后，我们将测试骨细胞凋亡是否是通过使用泛as-蛋白酶抑制剂抑制雌激素戒断和废除小鼠模型中骨质细胞凋亡来抑制骨细胞的“常见最终途径”，用于响应各种重塑刺激的骨吸收。公共卫生相关性。保持骨骼质量并防止骨骼组织脆弱性取决于骨骼的重塑，其中破骨细胞去除并取代了达到其功能寿命末尾的骨骼的微观区域。我们最近的发现表明，这种重塑以及绝经后和废除骨质疏松剂的营业额和骨质流失又取决于骨内骨细胞的调节死亡（凋亡）。这些发现表明，骨细胞凋亡可能是控制骨吸收的“常见最终途径”，以响应各种重塑刺激，并且也表明这种凋亡可能代表了调节衰老和骨质疏松症中骨质碎屑活性的新型治疗靶点。