TBONE and phosphonates in mineralization during aging

描述（由申请人提供）：矿化是有机物质被无机物浸渍的过程。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，特别是在老龄化人群中。例如，矿化不足会导致骨质疏松症和骨癌进展，而矿化升高会导致动脉粥样硬化和肾脏疾病等血管疾病。氮双膦酸盐（nbp）是治疗这些疾病的最常用药物，其作用机制尚不清楚。通过对人类单倍体细胞的基因筛选，我们发现了几个功能丧失导致对细胞毒性作用产生抗性的基因

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.