Schnurri-3 Inhibitors: specific inducers of adult bone formation

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DESCRIPTION (provided by applicant): In a normal physiological state the skeletal system provides mobility, protection for vital organs and serves as an essential environment in which hematopoiesis can occur [1]. To achieve these functions, the skeleton exists in a dynamic equilibrium characterized by continuous osteoclast-mediated resorption of bone and osteoblast- mediated bone deposition [2]. Maintenance of this homeostatic remodeling is disrupted during aging leading to debilitating bone loss referred to as osteoporosis that affects over 10 million individuals in the United States [3]. As an individual ages, the progression of this disease results in an increased incidence of fracture that results in serious health consequences [4]. Since few therapeutic options are available for the prevention or treatment of osteoporosis, our goal is to develop novel mechanism-based treatments that increase anabolic bone formation and prevent bone loss. We have recently identified Schnurri-3 (Shn3), a member of the Schnurri family of large zinc-finger proteins, as an essential regulator of adult bone formation [5]. Our generation and subsequent analysis of mice bearing a null mutation in Shn3 (Shn3-/- mice) revealed a profound high-bone mass phenotype that arises through augmented osteoblast activity and is characterized by greatly increased rates of bone formation. The osteosclerotic phenotype observed in Shn3-/- mice does not affect skeletal morphology since its onset is postnatal. However, the loss of Shn3 renders these mice refractory to the age-associated loss in bone that occurs in control mice. The characteristics of Shn3-/- bone: increased bone anabolic activity, preservation of normal morphogenesis, mineralization and biophysical properties suggest that this protein is an ideal therapeutic target for the treatment of certain skeletal disorders. Unfortunately, structural analysis of Shn3 has revealed a dearth of functional domains within this protein that are suitable for drug targeting. We have, however, demonstrated that shRNA targeting of the 3'UTR of Shn3 reduces protein levels and augments osteoblast function in vitro. Furthermore, we have determined that post-transcriptional blockade of Shn3 results in increased bone mass in vivo. Therefore, we have designed a series of cell-based assays that will allow for the identification of chemical probes that selectively reduce Shn3 protein levels through a post- transcriptional mechanism targeting the 3'UTR of this gene. The identification of compounds that decrease Shn3 levels would provide a valuable therapeutic approach to prevent the destructive bone loss associated with osteoporosis. PUBLIC HEALTH RELEVANCE: Osteoporosis is a debilitating disease of the skeletal system that currently affects over 10 million individuals in the United States. Disease progression results in an increased incidence of fracture that results in serious health consequences and will present an expanding source of morbidity and mortality in an aging global population. While a few classes of medications are available to either prevent bone loss or increase bone formation in the setting of osteoporosis or cancer, current therapeutics are far from ideal due to toxic side effects, intolerance, or prohibitive cost. The ultimate goal of this proposal is to develop mechanism-based treatments to prevent bone loss and to increase anabolic bone formation. 2