Targeting multiple Wnt inhibitors for synergistic anabolic action in the skeleton

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Project Summary/Abstract Low bone mass disease is a major public health concern, particularly among the elderly and middle-age post- menopausal women. There is growing interest in treating low bone mass disease using anabolic rather than anti-catabolic approaches, of which there are very few options. Recently, FDA approved the first bone anabol- ic agent outside of the PTH/PTHrP class—Evenity (romosozumab)—to treat patients at high risk of fracture. This antibody inhibits secreted sclerostin, preventing it from binding and antagonizing the Wnt co-receptors LRP5 and LRP6. The result is a stimulation of the downstream β-catenin pathway, and ultimately, anabolic action in bone tissue. However, unwanted side effects of romosozumab, including increased risk of cardio- vascular disease, were found during the phase III clinicals trials, prompting the FDA to assign a “black box warning” to romo, alerting prescribers and patients to the risks. My graduate studies will focus on making sclerostin inhibition much more potent, particularly in cortical bone, so that much lower doses of the agent are required to achieve the same (or better) response, while minimizing side effects. I will investigate this oppor- tunity by testing the ability of Wise inhibition (another secreted cysteine knot protein) to synergistically im- prove sclerostin antibody-mediated bone gain in the cortex. A similar strategy, using sclerostin and Dkk1 co- inhibition, is highly efficacious for synergistically improving cancellous bone. I will test the sclerostin/Dkk1 combination in an aging model. Through the training program described in the application, I will gain profi- ciency in conducting animal drug studies, working with mutant mouse models, numerous endpoint analyses, high throughput sequencing, microRNA profiling, large dataset analysis, and translational aging studies in mice. These training opportunities will be accomplished through 3 specific aims: (Aim 1) to determine the synergistic osteoanabolic action of Sost and Wise co-deletion/co-inhibition; (Aim 2) to determine the changes in osteocytic expression of secreted Wnt inhibitors (and other families) when Sost/sclerostin is disabled; and (Aim 3) to determine the efficacy of sclerostin and Dkk1 co-inhibition in improving cancellous bone in an aging model. I anticipate that these activities and pursuit, in addition to the other training activities described in the application, will significantly enhance my ability to lead an independent scientific career at an academic insti- tution, focusing on musculoskeletal biology problems that deteriorate human health.