The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture

摘要 非典型股骨骨折（AFFs）是一个主要的临床问题，无论是对患者遭受他们， 因为它们对患者接受治疗的意愿有着巨大的影响 有效的治疗骨质疏松的药物。此外，尽管AFF与长期 在使用双磷酸盐（BP）治疗的情况下，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，形成这种情况的基础和/或 通过增加对BP的敏感性使某些患者易患AFF。鉴定罕见突变， 易患AFF，特别是在用BP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治疗骨折。因此，了解基因和 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， 已知AFF的发病机制，没有AFF或骨干易感性的动物模型 骨折可用。值得注意的是，Diez-Perez博士团队最近的一项潜在突破可能会为 有机会采取初步措施填补这一知识空白。具体来说，3个姐妹篇的外显子组测序 患有AFFS的BPs治疗者在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，BPs抑制骨吸收的靶向途径。 此外，3例无关患者中的1例和一个单独的队列显示CYP 1A 1突变， GGPS和法尼基焦磷酸酶合酶（FPPS）也已确定在2例患者， 成骨不全（OI）V型进一步表明该途径与骨脆性之间的联系。的事实 这一途径是含氮双膦酸盐的靶点，这强烈表明， 通过模拟/放大BP作用，突变可能使患者易患AFFs。在这里，我们将测试 假设参与甲羟戊酸途径的一种或多种关键酶的突变容易导致 AFF，表现为BP治疗后骨干脆性增加 目的1）体外：确定Ggps 1和/或Cyp 1A 1突变是否复制以及如何复制 在3例AFF姐妹篇中观察到AFF对OC、OB和OCY的分化和功能的影响， 对含氮双膦酸盐的反应。 目的2）体内：确定具有杂合Ggps 1和/或Cyp 1A 1缺失的小鼠是否表现出 OVX和NBP治疗前和/或后骨干脆性。 虽然该途径的突变可能仅构成AFF患者的一个亚组，但该提议 可以验证特定遗传改变形成AFFs背景的概念，并提供第一个， 即使可能不完美，动物模型来理解这些有害骨折的机制。

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.