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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 “一分预防胜过一分治疗”这句话非常适用于绝经后骨质疏松症。绝经后，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发生。良好的预防策略可以消除骨质流失的增加不会过度抑制骨转换，也不会产生脱靶效应。雌激素替代疗法有效预防更年期骨质流失，但妇女健康倡议暴露了 ERT 的风险，并且在很大程度上作为预防策略已被放弃。 ERT 等 SERM 会增加 DVT 风险。长期使用双磷酸盐会增加非典型骨折的风险。为了解决这一治疗差距，我们提出了一个大胆的新方案基于集落刺激因子 1 生物学的策略。集落刺激因子 1 (CSF1) 是成骨细胞释放的主要集落刺激因子，在除了 RANKL 之外，破骨细胞的形成绝对需要。 CSF1 有两种主要亚型，膜结合亚型 (mCSF1) 和可溶性或循环亚型 (sCSF1)。 sCSF1 同工型具有独特的羧基末端延伸。雌激素的撤除选择性上调成骨细胞中的 sCSF1，而 mCSF1 没有变化。重要的是，针对 CSF1 的同种型不加区别的中和抗体可以完全防止卵巢切除术（OVX）引起的小鼠骨质流失。然而，阻断 CSF1 的两种亚型并不是可行的雌激素缺乏性骨质流失的预防策略，因为正常破骨细胞生成需要 CSF1。我们发现体内选择性删除sCSF1不会引起表型，不会改变骨的基础率周转，但可以保护小鼠免受 OVX 引起的骨质流失。这些数据表明 sCSF1 作为一种新型治疗药物目标是防止雌激素缺乏性骨质流失。该 R21 将检验选择性抑制的假设 CSF1 的可溶性异构体可防止雌激素缺乏性骨质流失，而不影响正常的骨质流失骨重塑或骨质量。在具体目标 1 中，将采用噬菌体展示抗体选择快速开发一种抗体，通过靶向 sCSF1 独特的 73 个氨基酸 C 端来选择性抑制 sCSF1 那个异构体。在具体目标 2 中，中和抗体施用的剂量和时间完全符合预防 OVX 野生型小鼠骨质流失，首先使用连续体内 DXA 骨密度进行测定 OVX 野生型小鼠的测量。用雌激素治疗的 OVX 动物和 OVX-sCSF1-/- 小鼠将作为控制。使用防止 BMD 相对于基线、OVX 和 Sham-OVX 野生型动物发生变化的方案将用中和抗体或同种型匹配对照抗体处理4周。综合骨密度和身体成分测量，以及离体 microCT、生物化学、生物力学和将进行组织形态计量学分析。为了确保足够的严谨性，这些研究将在两种不同品系的小鼠。如果成功，这些研究将为一种全新的预防方法提供证据绝经后骨质流失开始之前。