An ounce of prevention: stopping menopausal bone loss before it starts

一盎司的预防：在更年期骨质流失开始之前阻止它

基本信息

批准号：
10324591
负责人：
KARL Leonard INSOGNA
金额：
$ 18.24万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324591
关键词：
Address Adherence Affect Affinity Alternative Splicing Amino Acids Animals Antibodies Antigens Aphorisms Apoptosis Bacteria Binding Biochemical Biology Biomechanics Blocking Antibodies Body Composition Bone Density Bone remodeling CSF1R gene Cells Clinical Colony-Stimulating Factors Data Development Dose Dual-Energy X-Ray Absorptiometry Ensure Estrogen Replacement Therapy Estrogen Therapy Estrogens Fab Immunoglobulins Fracture Goals Hip Fractures Homeostasis Human Immunoglobulins Innate Bone Remodeling Insecta Kinetics Lead Libraries Macrophage Colony-Stimulating Factor Measurement Mechanics Mediating Membrane Menopause Molecular Mouse Strains Mus Mutagenesis Osteoblasts Osteoclasts Osteoporosis Ovariectomy Phage Display Phenotype Play Postmenopausal Osteoporosis Prevention Prevention strategy Production Property Protein Isoforms Protocols documentation Recombinants Regimen Reporting Risk Role Selective Estrogen Receptor Modulators Series Skeleton TNFSF11 gene Techniques Technology Testing Therapeutic Wild Type Mouse Withdrawal Woman Women&apos s Group Women&apos s Health antigen binding base bisphosphonate bone bone loss bone quality bone turnover cytokine experimental group expression vector in vivo inhibitor lead candidate microCT neutralizing antibody new therapeutic target osteoclastogenesis prevent receptor release factor skeletal stoichiometry

项目摘要

Summary The aphorism “an ounce of prevention is worth a pound of cure” very much applies to postmenopausal osteoporosis. Immediately following menopause, bone loss rates can reach as high as 3-4% per year. At present, there is no acceptable way to prevent this. A good prevention strategy would abrogate the increase in bone loss without over-suppressing bone turnover and without off-target effects. Estrogen replacement therapy effectively prevents menopausal bone loss, but the Women’s Health Initiative exposed the risks of ERT and it has largely been abandoned as a preventive strategy. SERMs like ERT increase the risk of DVT. The long-term use of bisphosphonates increases the risk of atypical fracture. To address this treatment gap, we propose a bold new strategy, based on the biology of Colony Stimulating Factor 1. Colony Stimulating Factor 1 (CSF1) is the principal colony stimulating factor released by osteoblasts and, in addition to RANKL, is absolutely required for osteoclast formation. There are two major isoforms of CSF1, a membrane-bound isoform (mCSF1) and a soluble, or circulating, isoform (sCSF1). The sCSF1 isoform has a unique carboxy-terminus extension. Withdrawal of estrogen selectively up-regulates sCSF1 in osteoblasts, while mCSF1 is unchanged. Importantly, an isoform-indiscriminate neutralizing antibody to CSF1 completely prevents ovariectomy (OVX)-induced bone loss in mice. However, blocking both isoforms of CSF1 is not a viable preventive strategy for estrogen-deficiency bone loss, because CSF1 is required for normal osteoclastogenesis. We found that selectively deleting sCSF1 in vivo causes no phenotype, does not change the basal rate of bone turnover, but protects mice against OVX-induced bone loss. These data point to sCSF1 as a novel therapeutic target to prevent estrogen-deficiency bone loss. This R21 will test the hypothesis that selective inhibition of the soluble isoform of CSF1 protects against estrogen-deficiency bone loss without affecting normal bone remodeling or bone quality. In Specific Aim 1, phage display antibody selection will be employed to rapidly develop an antibody that selectively inhibits sCSF1 by targeting the unique 73 amino acid c-terminus of that isoform. In Specific Aim 2, the dose and timing of neutralizing antibody administration that completely prevents bone loss in OVX wild type mice will first be determined using serial in vivo DXA bone density measurements in OVX wild type mice. OVX animals treated with estrogen and OVX-sCSF1-/- mice will serve as controls. Using the protocol that prevents a change in BMD from baseline, OVX and Sham-OVX wild type animals will be treated with neutralizing antibody or isotype matched control antibody for 4 weeks. Comprehensive BMD and body composition measurements, as well as ex vivo microCT, biochemical, biomechanical and histomorphometric analyses will be undertaken. To ensure adequate rigor, these studies will be performed in two different strains of mice. If successful, these studies will provide evidence for an entirely new way to prevent postmenopausal bone loss before it begins.

概括格言“一盎司的预防值得一磅治愈”非常适用于绝经后骨质疏松症。更年期后，骨质流失率每年可高达3-4％。现在，没有可接受的方法来防止这种情况。良好的预防策略将消除骨质流失的增加没有过度抑制的骨骼更新，也没有脱靶效应。雌激素替代疗法有效防止更年期的骨质流失，但妇女的健康计划暴露了ERT的风险，它在很大程度上已经被放弃为预防策略。像ERT这样的Serms增加了DVT的风险。长期使用双膦酸盐增加了非典型裂缝的风险。为了解决此治疗差距，我们提出了一个大胆的新策略，基于菌落刺激因子1的生物学。菌落刺激因子1（CSF1）是成骨细胞释放的主要菌落刺激因子，在除了RANKL，破骨细胞形成绝对必需。 CSF1有两个主要同工型膜结合的同工型（MCSF1）和固体或循环的同工型（SCSF1）。 SCSF1同工型具有独特的羧基末端扩展。雌激素的戒断有选择地上调成骨细胞中的SCSF1，而 MCSF1没有改变。重要的是，与CSF1的同工型诱导中和抗体完全防止卵巢切除术（OVX）诱导的小鼠骨质流失。但是，阻止CSF1的两种同工型不是可行的雌激素缺陷骨质流失的预防策略，因为CSF1是正常破骨细胞生成所必需的。我们发现，在体内选择性删除SCSF1不会引起任何表型，不会改变骨骼的基本速率营业额，但可以保护小鼠免受OVX引起的骨质流失。这些数据指向SCSF1是一种新的疗法。防止雌激素缺陷骨质流失的目标。该R21将测试选择性抑制的假设 CSF1的固体同工型可防止雌激素缺陷骨质流失而不影响正常骨骼重塑或骨质质量。在特定目标1中，噬菌体显示抗体选择将被雇用为快速开发一种通过靶向独特的73氨基酸C末端的抗体，该抗体有选择地抑制SCSF1 那是同工型。在特定的目标2中，完全中和抗体给药的剂量和时间完全首先使用串行DXA骨密度确定OVX野生型小鼠的骨质流失 OVX野生型小鼠的测量。用雌激素和OVX-SCSF1 - / - 小鼠处理的OVX动物将作为控件。使用防止基线，OVX和Sham-ovx野生动物的BMD变化的方案将用中和抗体或同型对照抗体进行4周处理。全面的BMD 身体成分测量以及离体微观，生化，生物力学和将进行组织形态学分析。为了确保足够的严格性，将在两种不同的小鼠菌株。如果成功，这些研究将为防止一种全新的方式提供证据绝经后骨质损失开始。