There is a clear need for new therapies that improve bone mass and reduce bone loss. In order to provide clinicians with a broader range of pharmacologic choices to suit their patients' particular needs for skeletal therapies, it is crucia that we pursue novel biological mechanisms in bone that might be beneficial to skeletal health. We have identified a potentially high?yield anabolic target that is novel to the skeletal researc community. The target is Nuclear Protein 1 (Nupr1), also known as protein 8 (p8) and candidate of metastasis?1 (com1). We identified this target in bone from an in vivo screen of differentiall regulated genes in several mouse models of Osteogenesis Imperfecta (OI). We phenotyped a small sample of femurs from Nupr1?/? mice via ?CT, and found a high bone mass phenotype. While our sample size is small, the data are suggestive that Nupr1 is a novel target in bone that ultimately could be manipulated to improve skeletal properties in patients. Based on our preliminary data, we hypothesize that Nupr1 regulates bone mass. To address this hypothesis, we have articulated two aims.
In Aim 1, we will confirm the high bone mass phenotype in Nupr1?/? mice and determine the mechanism of increased bone mass (increased bone formation, reduced resorption, or both).
This aim will provide verification that the skeletal effec we previously observed in our small femur sample is reproducible using adequate sample sizes, and it will guide our investigation of mechanism of action for Nupr1, in terms of altered resorption axis, altered formation axis, or both.
In Aim 2, we will determine the molecular pathways in which Nupr1 participates. We will conduct RNAseq experiments in Nupr1?/? and Nupr1+/+ mice to identify mRNA transcripts and splice?forms whose abundances are altered by Nupr1 inhibition.
This aim will allow us to focus on particular molecular mechanisms that Nupr1 might alter in the regulation of bone mass, ultimately yielding other novel targets for therapy.
Bone fragility is a major public health concern. Clinicians continue to express the need for new anabolic therapies in order to provide them with a means to stimulate new bone formation and restore lost bone in their most at?risk patients. We have identified a new molecular target in bone that could provide a new platform for skeletal therapy in patients.