First Author | Yadav VK | Year | 2008 |
Journal | Cell | Volume | 135 |
Issue | 5 | Pages | 825-37 |
PubMed ID | 19041748 | Mgi Jnum | J:146078 |
Mgi Id | MGI:3836667 | Doi | 10.1016/j.cell.2008.09.059 |
Citation | Yadav VK, et al. (2008) Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135(5):825-37 |
abstractText | Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass. |