Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum

Vijay K. Yadav, Je Hwang Ryu, Nina Suda, Kenji F. Tanaka, Jay A. Gingrich, Günther Schütz, Francis H. Glorieux, Cherie Y. Chiang, Jeffrey D. Zajac, Karl L. Insogna, J. John Mann, Rene Hen, Patricia Ducy, Gerard Karsenty

Research output: Contribution to journalArticle

604 Citations (Scopus)

Abstract

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 β-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 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 potential therapies to increase bone mass.

Original languageEnglish
Pages (from-to)825-837
Number of pages13
JournalCell
Volume135
Issue number5
DOIs
Publication statusPublished - 2008 Nov 28

Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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