ATRAID, a genetic factor that regulates the clinical action of nitrogen-containing bisphosphonates on bone.
2018
Nitrogen-containing
bisphosphonates(N-BPs), such as alendronate (Fosamax), are the mostly widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. In the last few years, widespread use of N-BPs has been challenged due to the risk of rare but significant side effects such as atypical
femoral fracturesand
osteonecrosisof the
jaw. N-BPs bind to and inhibit
farnesyl diphosphate synthase(FDPS), resulting in defects in protein
prenylation. Yet it remains poorly understood what other cellular targets N-BPs might have. Herein, we perform genome-wide studies in cells and patients to identify the gene, ATRAID, that functions with FDPS in a novel pathway we name the TBONE (Target of
Bisphosphonates) pathway. Loss of ATRAID function results in selective resistance to NBP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of
prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in a model of postmenopausal osteoporosis. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.
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