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Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.

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.

Pubmed ID: 19041748


  • Yadav VK
  • Ryu JH
  • Suda N
  • Tanaka KF
  • Gingrich JA
  • Sch├╝tz G
  • Glorieux FH
  • Chiang CY
  • Zajac JD
  • Insogna KL
  • Mann JJ
  • Hen R
  • Ducy P
  • Karsenty G



Publication Data

November 28, 2008

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK067936
  • Agency: NIDDK NIH HHS, Id: R01 DK067936-04

Mesh Terms

  • Animals
  • CREB-Binding Protein
  • Duodenum
  • Female
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Mice
  • Osteogenesis
  • Receptor, Serotonin, 5-HT1B
  • Serotonin
  • Tryptophan Hydroxylase