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O'Shea Lab > People > Tim Peterson

Function and Translational Potential of TBONE: A Regulator of Bone /td>
Tim Peterson <trpeters@fas>
There is growing recognition that aberrant tissue mineral deposition has a causal role in the morbidity and mortality of aging. Decreased mineralization, particularly of calcium phosphate in bones, is prevalent in postmenopausal women and in breast and prostate cancer patients with bone metastases. In addition, excessive calcification is seen in vascular diseases such as atherosclerosis and renal artery dysfunction linked to renal failure. A frontline treatment for several diseases afflicting bone is a drug class known as nitrogenous bisphosphonates (NBPs). To provide insight into how NBPs work, we performed loss of function screens in human haploid cells to identify human genes essential for the anti-proliferative effects of NBPs. In screening with the commonly prescribed NBP, Alendronate (Fosamax®), we identified several genes not previously connected to calcium phosphate metabolism, including the poorly characterized gene, henceforth referred to as TBONE (Target of BisphOsphonate NitrogEnous). Cells lacking TBONE are highly resistant to biochemical responses correlated with NBP therapeutic efficacy, including downregulation of intracellular ATP levels and protein prenylation. We also find that TBONE is required for several signaling events relevant to tissue mineralization, including cellular NBP accumulation, toxicity, and osteogenesis, the deposition of bone material. We are currently developing therapeutic antibodies directed against TBONE to eventually treat prostate cancer bone metastasis. Our research seeks to better understand and introduce a novel class of therapeutics for an assortment of diseases of extracellular etiology involving mineral deposition.

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