The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture

GGPS1和CYP1A1突变在非典型股骨骨折中的作用

• 批准号: 10055985
• 负责人: ROLAND E BARON
• 金额: $ 20.34万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055985
• 关键词: Adverse event; Affect; Aftercare; Animal Model; Biomechanics; Bone Resorption; Bone remodeling; CRISPR/Cas technology; CYP11A1 gene; CYP1A1 gene; Cell physiology; Cholesterol; Clinical; DNA Sequence Alteration; Data; Diphosphates; Enzymes; Estradiol; Exhibits; Femoral Fractures; Femur; Fracture; Functional disorder; Funding; Funding Mechanisms; Future; Genetic; Grant; Heterozygote; Human; Impairment; In Vitro; Individual; Knowledge; Link; LoxP-flanked allele; Molecular; Mus; Mutation; Nitrogen; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis Imperfecta; Osteoporosis; Osteoporotic; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Postmenopause; Predisposition; Prevention; Property; Provider; Risk; Role; Sister; Skeleton; Source; Testing; Therapeutic; Vitamin D; Woman; bisphosphonate; bone cell; bone fragility; cell type; cohort; exome sequencing; fragility fracture; high reward; high risk; in vivo; knock-down; mevalonate; osteoporosis with pathological fracture; patient subsets; prevent; pyrophosphatase; response; small hairpin RNA; tool; willingness

Abstract Atypical Femoral Fractures (AFFs) are a major clinical problem, both for the patients that suffers them and for the overall osteoporotic population because of their enormous impact on patients' willingness to be treated with effective osteoporosis medications. Also, although AFF has been associated with long-term bisphosphonates (BPs) treatment, a number of patients (up to 30%) who suffer AFF have never taken BPs. This observation suggests the presence of rare genetic mutations that form the basis of this condition and/or predispose certain patients to AFF by increasing their sensitivity to BPs. Identification of rare mutations that predispose to AFF, in particular after treatment with BPs, would permit the prevention of many of these fractures by selecting the appropriate treatment for such patients. Thus, understanding the genetic and molecular basis of AFF and diaphyseal fragility is of the utmost clinical importance. As of today, little is known about the pathogenesis of AFF and no animal model of AFF or of susceptibility to diaphyseal fractures is available. Notably, a recent potential breakthrough by Dr. Diez-Perez group may offer the opportunity to make initial steps in filling this knowledge gap. Specifically, exome sequencing in 3 sisters treated with BPs who suffered AFFs has identified mutations, shown or predicted to impair function, in 3 components of the mevalonate pathway, the very pathway targeted by BPs to inhibit bone resorption. Furthermore, 1 of 3 unrelated patients and a separate cohort showed mutations in CYP1A1, and mutations in GGPS and Farnesyl pyrophosphatase synthase (FPPS) have also been identified in 2 patients with Osteogenesis Imperfecta (OI) type V further suggesting a link between this pathway and bone fragility. The fact that this pathway is the target of nitrogen-containing bisphosphonates strongly suggests that these mutations, by mimicking/amplifying BPs action, may predispose patients to AFFs. Here, we will test the hypothesis that mutations in one or more of the key enzymes involved in the mevalonate pathway predispose to AFF, evidenced as increased diaphyseal fragility after BP treatment Aim 1) In vitro: Determine whether and how replication of the Ggps1 and/or Cyp1A1 mutations observed in the 3 sisters with AFF affect OC, OB and OCY differentiation and function and their responses to nitrogen-containing bisphosphonates. Aim 2) In vivo: Determine whether mice with heterozygous Ggps1 and/or Cyp1A1 deletion exhibit diaphyseal fragility before and/or after OVX and treatment with NBPs. Although mutations in this pathway probably constitute only a subset of the patients with AFF, this proposal may validate the concept that specific genetic alterations form the background of AFFs and provide the first, even though potentially imperfect, animal model to understand the mechanisms of these deleterious fractures.

抽象的 非典型股骨骨折（AFF）对于患者和患者来说都是一个主要的临床问题 对于整个骨质疏松人群，因为它们对患者接受治疗的意愿产生巨大影响 使用有效的骨质疏松药物。此外，尽管 AFF 与长期 在双磷酸盐 (BP) 治疗中，许多患有 AFF 的患者（高达 30%）从未服用过 BP。 这一观察结果表明存在罕见的基因突变，这些突变构成了这种情况的基础和/或 通过增加某些患者对 BP 的敏感性，使他们易患 AFF。鉴定罕见突变 易患 AFF，特别是在使用 BP 治疗后，可以预防其中许多 通过为此类患者选择适当的治疗方法来治疗骨折。因此，了解遗传和 AFF 和骨干脆性的分子基础具有极其重要的临床意义。到今天为止，已经很少了 已知 AFF 的发病机制，但没有 AFF 或骨干易感性的动物模型 骨折是可用的。值得注意的是，Diez-Perez 博士小组最近的一项潜在突破可能会提供 采取初步措施来填补这一知识空白的机会。具体来说，三姐妹的外显子组测序 患有 AFF 的 BP 治疗者已在 3 例中发现了突变，显示或预测会损害功能 甲羟戊酸途径的组成部分，该途径正是 BP 抑制骨吸收的目标途径。 此外，3 名不相关的患者和一个单独的队列中的 1 名显示 CYP1A1 突变，以及 CYP1A1 突变 GGPS 和法呢基焦磷酸酶合酶 (FPPS) 也在 2 名患有 V 型成骨不全 (OI) 进一步表明该途径与骨脆性之间存在联系。事实 该途径是含氮双膦酸盐的目标，强烈表明这些 突变通过模仿/放大 BP 的作用，可能使患者易患 AFF。在这里，我们将测试 甲羟戊酸途径中涉及的一种或多种关键酶的突变假设 至 AFF，表现为 BP 治疗后骨干脆性增加 目标 1) 体外：确定 Ggps1 和/或 Cyp1A1 突变是否以及如何复制 在患有 AFF 的 3 姐妹中观察到影响 OC、OB 和 OCY 分化和功能及其作用 对含氮双膦酸盐的反应。 目标 2) 体内：确定杂合 Ggps1 和/或 Cyp1A1 缺失的小鼠是否表现出 OVX 和 NBP 治疗之前和/或之后的骨干脆性。 尽管该通路中的突变可能仅构成 AFF 患者的一个子集，但该提议 可以验证特定基因改变形成 AFF 背景的概念，并提供第一个， 尽管可能不完美，但动物模型可以了解这些有害骨折的机制。