Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum

Loss- and gain-of-function mutations in the broadly expressed gene LDL receptor-related protein 5 (Lrp5) affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of β-catenin does not affect bone formation.

Instead, the authors of this study [1] show here that Lrp5 inhibits expression of tryptophan hydroxylase 1 (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 β-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 alternative avenues to increase bone mass.

1. Yadav VK et al. Cell. 2008;135: 825–837.