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.

Public Health Relevance

Phosphonates are naturally abundant in our food and some, such as the bisphosphonate Fosamax(R), are among the most commonly used medications in aging populations. The proposed research will investigate a newly discovered gene, TBONE (Target of BisphOsphonate NitrogEnous) that is critical for the therapeutic effects of phosphonates. This work suggests an entirely new understanding of important medicines and also a new therapeutic approach in aging-one that is dietary, and likely considerably safer than that of taking bisphosphonates.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Career Transition Award (K99)
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National Institute on Aging Initial Review Group (NIA)
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Williams, John
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Harvard University
Schools of Arts and Sciences
United States
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Yu, Zhou; Surface, Lauren E; Park, Chong Yon et al. (2018) Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates. Elife 7:
Horlbeck, Max A; Xu, Albert; Wang, Min et al. (2018) Mapping the Genetic Landscape of Human Cells. Cell 174:953-967.e22