Lrp5 and bone formation : A serotonin-dependent pathway.
Lrp5, the mutated gene in osteoporosis pseudoglioma (OPPG) and the high bone-mass syndrome (HBM), regulates bone formation, while beta-catenin, the molecular node of Wnt signaling, regulates bone resorption, suggesting that Lrp5 could act in a Wnt-independent manner. Using microarray and conditional gene deletion in mice, we showed that Lrp5 actually enhances bone formation by inhibiting the expression, in duodenum, of tryptophan hydroxylase 1, the rate-limiting enzyme in the serotonin biosynthetic pathway. Accordingly, serotonin circulating levels are high in Lrp5(-/-) mice and OPPG patients but low in HBM patients, and normalizing serum serotonin levels rescues the bone phenotype of the Lrp5(-/-) mice. We also showed that serotonin acts on osteoblasts through the Htr1b receptor and the transcription factor cAMP responsive element binding to inhibit their proliferation. This study shows that Lrp5 acts in gut cells, not in osteoblasts, to control bone formation via a Wnt-independent pathway and identifies a new hormone, serotonin, and a novel endocrine axis regulating bone mass. These findings may have important therapeutic implications for the treatment of low bone-mass disorders.
Yadav
Vijay K
VK
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Ducy
Patricia
P
D000818:Animals; D020868:Gene Silencing; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010012:Osteogenesis / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D012701:Serotonin