The mechanistic control of bone extracellular matrix material properties by TGFb

TGFb对骨细胞外基质材料特性的机械控制

• 批准号: 9119517
• 负责人: Tamara N Alliston
• 金额: $ 39.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119517
• 关键词: Actomyosin; Adrenal Cortex Hormones; Affect; Aging; Anabolism; Biochemical; Biological; Biomedical Engineering; Bone Matrix; Bone necrosis; Cells; Collagen; Communication; Couples; Cues; Data; Defect; Development; Disease; Enzymes; Exposure to; Extracellular Matrix; Fracture; Funding; Goals; Head; Health; Hindlimb; Histologic; Homeostasis; Human; In Vitro; Jaw; Lead; Ligands; MMP14 gene; Maintenance; Mandible; Mechanics; Mediating; Metalloproteases; Minerals; Molecular; Mus; Osteocytes; Osteolysis; Osteoporosis; Osteoradionecrosis; Outcome; Participant; Pathway interactions; Peptide Hydrolases; Phosphorylation; Process; Property; Prostaglandins; Regulation; Repression; Research; Resistance; Role; Signal Transduction; Skeleton; Steroids; Testing; Transforming Growth Factor beta; Work; bone; bone mass; bone quality; cellular targeting; diabetic; expectation; field study; improved; in vivo; inhibitor/antagonist; insight; loss of function; malignant mouth neoplasm; mineralization; novel; novel therapeutics; physical property; prevent; quantitative imaging; receptor; receptor expression; response; skeletal; skeletal disorder; therapy development

DESCRIPTION (provided by applicant): New therapies that protect or restore bone quality have great potential to significantly improve skeletal health. Development of these therapies requires the identification of the cellular and molecular mechanisms that regulate bone quality. Therefore, the long-term goal of this research is to identify mechanisms by which biological and physical cues control bone extracellular matrix (ECM) material properties. To that end, this renewal application builds on our discovery that TGFß regulates the material properties of bone ECM and remains one of just a handful of factors yet shown to do so. Recent work, supported by the first funding cycle, establishes osteocytes and MMP13 as key participants in the control of bone quality through a dynamic process called perilacunar remodeling (PLR). In PLR, osteocytes secrete proteases such as MMP13 to resorb the perilacunar bone matrix. PLR is essential for the maintenance of bone quality, systemic mineral homeostasis, and the canalicular channels that facilitate osteocyte nourishment, communication, and mechanosensation. Our recent data suggests that disruption of PLR in human bone may contribute to the bone fragility in diseases such as osteonecrosis of the femoral head or osteoradionecrosis of the jaw. However, major gaps surround the understanding of the role or regulation of PLR in healthy bone or in skeletal disease. Preliminary data raise the possibility that PLR is regulated by mechanical load and by TGFß, a mechanism that has the potential to couple the maintenance of bone quality by PLR to changing physical and biological demands on the skeleton. This proposal tests the hypothesis that osteocytes regulate bone ECM material properties through perilacunar remodeling in a load- and TGFß-dependent manner to control bone quality and cellular tension. Specifically, this project aims to: 1) determine the extent to which perilacunar remodeling is mechanosensitive and TGFß-regulated, 2) identify mechanisms by which mechanical load regulates the effects of TGFß on bone, and 3) determine the functional impact of PLR on bone ECM quality and osteocyte tension. PLR activity and regulation will be evaluated using a combination of histologic, radiologic, bioengineering, and molecular approaches. These studies will assess the effects on PLR of osteocyte-specific MMP13-deficiency, applied mechanical loads, and pharmacologic inhibition of the TGFß type I receptor. In vivo and in vitro gain and loss of function studies will be used to determine the extent to which these factors operate in an epistatic pathway. In addition, this project examines the effect of dynamically regulated perilacunar bone ECM material properties on osteocyte cellular tension, signaling, and function. This project is significant because it will elucidate the regulation of osteocyte mediated PLR and bone quality by TGFß and physical cues, revealing new mechanisms that can be therapeutically targeted to prevent bone fragility and maintain skeletal health.

描述（由适用提供）：保护或恢复骨质质量的新疗法具有显着改善骨骼健康的巨大潜力。这些疗法的发展需要鉴定调节骨质质量的细胞和分子机制。因此，这项研究的长期目标是确定生物学和物理线索控制骨外基质（ECM）材料特性的机制。为此，这种续订应用是基于我们发现TGFß调节骨ECM的材料特性的基础，并且仍然是少数尚未证明的因素之一。在第一个融资周期的支持下，最近的工作确立了骨细胞和MMP13，作为通过称为Perilacunar重塑（PLR）的动态过程控制骨骼质量的关键参与者。在PLR中，骨细胞秘密蛋白酶（例如MMP13）吸收perilacunar骨基质。 PLR对于维持骨骼质量，全身矿物质稳态以及促进骨细胞营养，通信和机制的管道通道至关重要。我们最近的数据表明，人骨中PLR的破坏可能导致疾病的骨骼脆弱性，例如股骨头的抑制作用或颌骨的骨adiio骨质。但是，围绕对健康骨骼或骨骼疾病中PLR的作用或调节的理解或调节的主要差距。初步数据增加了PLR受到机械载荷和TGFß调节的可能性，TGFß有可能通过PLR来维持骨骼质量以改变骨骼对物理和生物学需求。该建议检验了以下假设，即骨细胞通过载膜纳尔重塑以载荷和TGFß依赖性方式调节骨ECM材料特性，以控制骨骼质量和细胞张力。具体而言，该项目的目的是：1）确定机械上的Perilacunar重塑的程度和TGFß调节，2）确定机械负荷调节TGFß对骨骼的影响的机制，3）确定PLR对骨ECM质量和骨细胞张力的功能影响。 PLR活性和调节将通过组织学，放射学，生物工程和分子方法的组合进行评估。这些研究将评估对骨细胞特异性MMP13缺乏，应用机械载荷和对TGFßI型受体的药物抑制的影响。体内和体外增益和功能研究的丧失将用于 确定这些因素在上位途径中的工作程度。此外，该项目还研究了动态调节的围骨骨ECM材料特性对骨细胞细胞张力，信号传导和功能的影响。该项目很重要，因为它将通过TGFß和物理提示来阐明骨细胞介导的PLR和骨骼质量的调节，从而揭示了可以热靶向的新机制，以防止骨骼脆弱性并保持骨骼健康。