Deciphering Mechanisms of Nitrogen-Containing Bisphosphonates - Admin Supplement

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Abstract Osteoporosis and low bone mass (osteopenia) are estimated to affect 55 percent of the American population over the age of 50; over 50 million people in total, with major consequences for the patients’ quality of life. The current standard treatment for osteoporosis is administration of nitrogen-containing bisphosphonates (NBPs). However, the mechanism by which these highly-charged drugs enter, traffic through, and reach their molecular targets and effect target cells is poorly understood. The long-term goal of this proposal is to deconstruct the molecular pathways essential for NBP response. To do this, we will build upon preliminary genetic studies by using cell assays and mouse models, as well as in vitro binding and functional assays to explore the interactions between NBPs and our identified targets. Our previous work utilized two distinct high-throughput genome-wide screens to identify over 200 genes required for the action of NBPs. The initial focus of our studies has been on the role of two genes, ATRAID and SLC37A3, that strongly affect the response to NBPs, and are likely to be required for the endocytic trafficking of these drugs. This proposal builds upon this to i) dissect how ATRAID and SLC37A3 facilitate NBP trafficking and their cellular function, ii) investigate the role of two transcription factors, associated by GWAS with changes in BMD, that when depleted may sensitize cells to the effects of NBPs, and iii) using conditional ATRAID knockout mice, investigate the mechanism by which these drugs are therapeutic for bone metastases. Together, these studies generate a broader picture of the molecular pathways that NBPs use to affect cells and tissues. This proposal focuses on a subset of identified genes, and will set the stage for future work determining how genes identified in drug screens may predict patient response to NBPs, including efficacy of treatment, dosage of NBPs needed, and adverse side effects. Moreover, this focus on understanding the mechanisms of an inexpensive, commonly prescribed drug will bring new perspectives and hypotheses to the development of treatment strategies for osteoporosis.