TBONE and phosphonates in mineralization during aging

矿化是有机物质被无机物浸透的过程。 物质。它对生物学是至关重要的，当它被破坏或过度激活时，有助于 对人类健康的影响，特别是对老龄化人口的影响。例如，矿化方面的不足 会导致骨质疏松症和癌症进展，而矿化增加则会导致 血管疾病，如动脉粥样硬化和肾脏疾病。MOST的作用机制 治疗其中几种疾病的常用药物类别是含氮二膦酸盐(Nbps)， 人们对此知之甚少。通过在人类细胞中的遗传筛选，我们鉴定了几个基因的缺失 功能导致对NBP、阿伦磷酸钠(Fosamax®)的细胞毒性作用产生抵抗。我们把它们命名为 含氮双膦酸类化合物的基因、靶标(TBONE1、TBONE2…)。我们证明了TBONE1 是由nbps触发的生化反应以及骨功能所必需的。内生性 含氮的磷酸盐(NPs)，在化学上与nbps有关，来自我们的饮食和 TBONE1依赖的微生物群对骨合成成骨细胞矿化的有效调控 举止。最后，TBONE1基因缺陷小鼠的体重较低，骨重建的标志物不受调控，而且 寿命缩短。这些发现表明，通过TBONE1作用的磷酸盐对组织至关重要 矿化作用。在这个方案中，我们将测试Tbone基因，目的如下：1)解剖 TBone分子相互作用机制的研究：2)TBONE1-膦酸根途径的阐明 小鼠的骨骼和血管系统。新的TBone基因的鉴定揭示了一种意想不到的新发现 对一些最广泛使用的药物，双膦酸类药物的了解和研究途径。 此外，自然生成的磷酸盐刺激矿化表明了一个重要的新的 对许多与衰老相关的疾病采取决定性和更安全的治疗方法。

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 cells we identified several genes whose loss of function led to resistance to the cytotoxic effects of the NBP, Alendronate (Fosamax®). We named these genes, Targets of BisphOsphonate NitrogEnous (heretofore TBONE1, TBONE2…). We show that TBONE1 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 TBONE1-dependent manner. Lastly, TBONE1 deficient mice have low body mass, deregulated markers of bone remodeling and reduced lifespan. These findings suggest that phosphonates acting through TBONE1 are critical for tissue mineralization. In this proposal, we will test TBONE genes with the following aims: 1) Dissection of the mechanisms of TBONE molecular interactions; 2) Elucidation of the TBONE1-phosphonate pathway in the bones and vasculature of mice. The identification of novel TBONE genes 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.