Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum: an entero-bone endocrine axis
By V. Yadav, Je-Hwang Ryu, N. Suda, Kenji Tanaka, J. Gingrich, G. Schütz, F. Glorieux, C. Chiang, J. Zajac, K. Insogna and 4 more. Cell, 2008
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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 novel therapies to increase bone mass.
Subfields: Gastroenterology, Nutrition and Dietetics, Surgery
View Paper: https://www.semanticscholar.org/paper/0da5c411bf6578c19d28e4e7687d9de27e375ba5
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Citations in the corpus
- Building strong bones: molecular regulation of the osteoblast lineage (2011, background): “By contrast, mice engineered to express a mutant form of LRP5 that causes high bone mass in humans also exhibit a high bone mas”
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- The Regulation of Differentiation in Mesenchymal Stem Cells (2010, positive): “…bone formation via indirect mechanisms, such as Htr1b (5-hydroxytryptamine [serotonin] receptor-1B)–CREB (cAMP response element-binding protein) (Yadav et al. , 2008), but also that the gain-of-function mutation in Lrp5 may not have an effect on bone density when expressed in mature…”
- Serotonin syndrome. (2014, background): “…migraine, and vomiting; more recently, it has been implicated in other processes such as bone metabolism, hemostasis, blood pressure control, anti-inflammatory action, and so on (Yadav et al. 2008; Tseng et al. 2013; Watts et al. 2012; Yu et al. 2008; Zhang et al. 2012; Beikmann et al. 2013).”
- Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling (2009, background): “derived Lrp5 controlled bone formation by inhibiting serotonin synthesis.((32)) Their data did not necessarily contradict the effect of sclerostin on Wnt/b-catenin.”
- Leptin regulation of bone mass, appetite and energy expenditure relies on its ability to inhibit serotonin synthesis in the brainstem (2009, neutral): “Thus, it is de facto a molecule with two distinct functional identities depending on its site of synthesis: a hormone when made in the gut and a neurotransmitter when made in the brain (Walther et al., 2003; Yadav et al., 2008).”
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- Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis (2015, neutral): “…reflexes (Gershon and Tack, 2007), platelet aggregation (Mercado et al., 264 Cell 161, 264–276, April 9, 2015 ª2015 Elsevier Inc. 2013), immune responses (Baganz and Blakely, 2013), and bone development (Chabbi-Achengli et al., 2012; Yadav et al., 2008), and cardiac function (Côté et al., 2003).”