NMUR2 in bone formation - Project Summary
The long-term goal of this project is to establish the molecular pathway used by Neuromedin-U (NMU) in the
negative regulation of bone formation. This is significant since studies in mice indicate NMU negatively regulates
bone formation in vivo, making the NMU pathway a potential therapeutic target for treating osteoporosis, a
disease that places individuals at enhanced risk for fracture, disability, and death. Hospitalizations for
osteoporotic fracture exceeds those for heart attack, stroke, and breast cancer, and direct medical costs for
osteoporosis in the US are estimated to be approximately $20 billion. Despite this, there are limited treatment
options for osteoporosis, particularly for long-term management of this chronic condition, and the available
pharmacological therapies have significant drawbacks. Consequently, there is an urgent need for developing
new therapeutic approaches for treating osteoporosis. The proposed R03 will follow a novel line of investigation
to examine the role of the NMU pathway in the restriction of bone formation. Work by this research team and
others demonstrates that endogenous NMU suppresses osteoblast differentiation and function; however, a poor
understanding of the molecular pathway utilized by NMU to suppress bone formation restricts translational
opportunities at present. This R03 proposal seeks to address this limitation by determining the functional role of
NMU Receptor 2 (NMUR2) in the skeleton in vivo and to test the hypothesis that NMUR2 is required for NMU-
mediated suppression of bone formation. Using a novel mouse line in which Nmur2 expression is lost in the
appendicular skeleton, we will examine the role of NMUR2 through quantification of bone mass, quantitative
histological analyses, serum markers of bone turnover, and high-throughput signaling arrays for examining
hundreds of potential effectors downstream of NMUR2 in bone. This project is an excellent fit for the goals of the
R03 funding mechanism in that 1) it provides a foundation for future projects in a novel line of investigation; 2) it
can be carried out in a short period of time with limited resources; 3) is relatively small in cost, scale, and duration;
4) and is self-contained. Moreover, upon completion, these findings will provide essential preliminary data for
future, larger scale studies aimed at complete characterization of the NMU signaling pathway in the skeleton,
which may identify novel strategies for inhibiting its effects through pharmacological means such as small
molecules or neutralizing antibodies.
