Greater Bone Formation of Y2 Knockout Mice Is Associated with Increased Osteoprogenitor Numbers and Altered Y1 Receptor Expression

Abstract

Germ line or hypothalamus-specific deletion of Y2 receptors in mice results in a doubling of trabecular bone volume. However, the specific mechanism by which deletion of Y2 receptors increases bone mass has not yet been identified. Here we show that cultured adherent bone marrow stromal cells from Y2����/���� mice also demon- strate increased mineralization in vitro. Isolation of two popula- tions of progenitor cell types, an immature mesenchymal stem cell population and a more highly differentiated population of progen- itor cells, revealed a greater number of the progenitor cells within the bone of Y2����/���� mice. Analysis of Y receptor transcripts in cul- tured stromal cells from wild-type mice revealed high levels of Y1 but not Y2, Y4, Y5, or y6 receptor mRNA. Interestingly, germ line Y2 receptor deletion causes Y1 receptor down-regulation in stro- mal cells and bone tissue possibly due to the lack of feedback inhi- bition of NPY release and subsequent overstimulation of Y1 recep- tors. Furthermore, deletion of Y1 receptors resulted in increased bone mineral density in mice. Together, these findings indicate that the greater number of mesenchymal progenitors and the altered Y1 receptor expression within bone cells in the absence of Y2 receptors are a likely mechanism for the greater bone mineral- ization in vivo and in vitro, opening up potential new treatment avenues for osteoporosis.