TBONE and phosphonates in mineralization during aging

描述(申请人提供)：矿化是有机物质被无机物浸透的过程。它对生物学至关重要，当它被破坏或过度激活时，会对人类健康产生广泛的影响，特别是在老龄化人口中。例如，矿化不足会导致骨质疏松症和癌症进展，而矿化增加会导致动脉粥样硬化和肾脏疾病等血管疾病。治疗其中几种疾病最常用的药物类--含氮二膦酸盐(NBP)的作用机制尚不清楚。通过在人类单倍体细胞中的遗传筛选，我们鉴定了几个功能丧失导致对细胞毒作用产生抗性的基因 在NBP中，Alendronate(Fosamax(R))，包括一个特征不佳的基因，我们将其命名为双膦酸盐含氮靶基因(此前为Tbone)。我们的研究表明，TBone对于NBPS引发的生化反应以及骨功能都是必需的。内源性含氮磷酸盐(NPs)在化学上与NBPS有关，来自我们的饮食和微生物群，以一种TBone依赖的方式有效地调节成骨细胞的矿化。最后，TBone缺乏的小鼠体重较低，骨骼重塑的标记物不受控制，寿命缩短。这些发现表明，通过TBone作用的磷酸盐对组织矿化至关重要。在这项提议中，我们将以以下目的验证这一假设：1)剖析TBone-膦酸盐分子相互作用的机制；2)阐明TBone-膦酸盐在小鼠骨骼和血管系统中的途径。TBone的鉴定表明了对一些最广泛使用的药物双膦酸类药物的意外新理解和研究途径。此外，天然生成的磷酸盐刺激矿化，为许多与衰老相关的疾病提供了一种重要的新决定因素和更安全的治疗方法。

DESCRIPTION (provided by applicant): Mineralization is a process through which an organic substance becomes impregnated by inorganic substances. It is critically important to biology and when disrupted or hyperactivated contributes to wide- ranging effects on human health particularly in aging populations. For example, deficiencies in mineralization contribute to osteoporosis and cancer progression in bone, whereas elevated mineralization contributes to vascular disease such as atherosclerosis and kidney disease. The mechanism of action of the most commonly used drug class for treating several of these conditions, Nitrogenous Bisphosphonates (NBPs), is poorly understood. Through genetic screening in human haploid cells we identified several genes whose loss of function led to resistance to the cytotoxic effects of the NBP, Alendronate (Fosamax(R)), including a poorly characterized gene we named Target of BisphOsphonate NitrogEnous (heretofore TBONE). We show that TBONE is required both for biochemical responses triggered by NBPs as well as for bone function. Endogenous nitrogenous phosphonates (NPs), which are chemically related to NBPs and come from our diet and microbiome, potently regulate mineralization in bone-synthesizing osteoblasts in a TBONE-dependent manner. Lastly, TBONE deficient mice have low body mass, deregulated markers of bone remodeling and reduced lifespan. These findings suggest that phosphonates acting through TBONE are critical for tissue mineralization. In this proposal, we will test this hypothesi with the following aims: 1) Dissection of the mechanisms of TBONE-phosphonate molecular interactions; 2) Elucidation of the TBONE-phosphonate pathway in the bones and vasculature of mice. The identification of TBONE suggests an unexpected new understanding of and path of investigation for some of the most widely used medications, bisphosphonates. Additionally, that naturally occurring phosphonates stimulate mineralization suggests an important new determinant and safer therapeutic approach for numerous aging-associated conditions.