TBONE and phosphonates in mineralization during aging

说明（由申请人提供）：矿化是一种有机物质被无机物质浸渍的过程。它对生物学至关重要，当被破坏或过度激活时，会对人类健康产生广泛影响，特别是在老龄化人群中。例如，矿化不足导致骨质疏松和骨癌症进展，而矿化升高导致血管疾病，如动脉粥样硬化和肾脏疾病。治疗这些疾病中的几种最常用的药物类别，含氮双膦酸盐（NBP）的作用机制知之甚少。通过在人类单倍体细胞中的遗传筛选，我们鉴定了几个基因，其功能丧失导致对细胞毒性作用的抗性 的NBP，阿仑膦酸钠（Fosamax（R）），包括一个我们命名为双膦酸盐NitrogEnous靶（迄今为止为TBONE）的表征不佳的基因。我们表明，TBONE是必需的生化反应引发的NBP以及骨功能。内源性含氮磷酸盐（NP）与NBP化学相关，来自我们的饮食和微生物组，以TBONE依赖性方式有效调节骨合成成骨细胞的矿化。最后，TBONE缺陷小鼠体重低，骨重建标志物失调，寿命缩短。这些发现表明，通过TBONE作用的膦酸盐对组织矿化至关重要。在本提案中，我们将测试这一假设，其目的如下：1）剖析TBONE-膦酸酯分子相互作用的机制; 2）阐明小鼠骨骼和血管中的TBONE-膦酸酯途径。TBONE的鉴定表明了对一些最广泛使用的药物双膦酸盐的意想不到的新理解和研究路径。此外，天然存在的膦酸盐刺激矿化表明了许多衰老相关疾病的重要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.