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: 10222572
• 负责人: ROLAND E BARON
• 金额: $ 22.09万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222572
• 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）是一个主要的临床问题，既适合患者的患者，又是 对于整体骨质疏松人群，由于对患者的愿意受到巨大影响 有效的骨质疏松药物。另外，尽管AFF与长期相关 双膦酸盐（BPS）治疗，许多患者（多达30％）的患者从未服用过BPS。 该观察结果表明存在罕见的遗传突变，这些突变构成了这种情况和/或 通过增加对BPS的敏感性，使某些患者容易使某些患者进行AFF。识别罕见突变 易感性，特别是在用BPS治疗后，将允许预防其中许多 通过为此类患者选择适当的治疗方法来骨折。因此，了解遗传和 AFF和diaphyseal脆弱性的分子基础是最重要的临床重要性。截至今天，几乎没有 知道AFF的发病机理，没有AFF的动物模型或易感性的动物模型 可骨折。值得注意的是，Diez-Perez Group博士最近的潜在突破可能会提供 有机会填补这一知识差距的初步步骤。具体来说，在三姐妹中进行外显子组测序 用遭受AFFS的BP处理已确定突变，显示或预测会损害功能，在3 大甲酸酯途径的成分，这是BPS靶向的途径以抑制骨吸收。 此外，3名无关患者中有1例和一个单独的队列显示了CYP1A1的突变，并在突变中发生突变。 在2例患者中，也已经确定 成骨的不完美（OI）类型V进一步暗示了该途径与骨骼脆弱性之间的联系。事实 该途径是含氮双膦酸盐的目标强烈表明这些途径 突变，通过模仿/扩增BPS作用，可能使患者容易受到AFF的影响。在这里，我们将测试 假设一种或多种涉及甲谷酸盐途径的关键酶中的突变易感性 aff，证明是BP处理后增加diaphyseal脆弱性 目标1）体外：确定GGPS1和/或CYP1A1突变的复制以及如何复制 在3个姐妹中观察到具有影响OC，OB和OCY分化和功能及其功能及其功能 对含氮双膦酸盐的反应。 目标2）体内：确定杂合GGPS1和/或CYP1A1缺失的小鼠是否展示 OVX之前和/或用NBP治疗前后的diaphyseal脆弱性。 尽管该途径中的突变可能仅构成AFF患者的一部分，但该提案 可以验证特定遗传改变构成AFF的背景并提供第一个的概念 即使潜在的不完美，动物模型也可以理解这些有害骨折的机制。