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.
Yadav
Vijay K
VK
Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Ryu
Je-Hwang
JH
Suda
Nina
N
Tanaka
Kenji F
KF
Gingrich
Jay A
JA
Schütz
Günther
G
Glorieux
Francis H
FH
Chiang
Cherie Y
CY
Zajac
Jeffrey D
JD
Insogna
Karl L
KL
Mann
J John
JJ
Hen
Rene
R
Ducy
Patricia
P
Karsenty
Gerard
G
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism*; D005260:Female; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D010012:Osteogenesis; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D050882:CREB-Binding Protein