? Project #3 The goal of this project is to characterize the influence on bone remodeling during adulthood and aging of extra-intestinal sites of expression of Tryptophan hydroxylase 1 (Tph1), the enzyme controlling the synthesis of two extracellular cues: serotonin and melatonin. Instead of the high bone mass/increased bone formation phenotype caused by Tph1 specific inactivation in gut cells we have observed that Tph1-/- mice show a mild increase in bone formation compensated by a mild increase in osteoclast number. This suggests that Tph1 expression outside the gut regulates the production of molecules that can counteract the effect on bone mass accrual caused by gut-derived serotonin. Although Tph1 is preferentially expressed in gut cells, its expression in the pineal gland is required for melatonin biosynthesis. Thus, a global inactivation of Tph1 causes an absence of both serotonin and melatonin. This led us to hypothesize that melatonin is a positive regulator of bone mass accrual that opposes the negative effect of gut- derived serotonin on bone formation. Consistent with this hypothesis, melatonin treatment of primary osteoblasts increases the expression of D-type cyclins, whose expression is instead down-regulated by gut- derived serotonin. Further analyses showed that melatonin could offset the effect of sympathetic signaling on CREB, ATF4 and their respective target genes in these cells. These preliminary studies suggest that melatonin could positively act on bone mass accrual by antagonizing the effect of both gut-derived serotonin and sympathetic signaling in osteoblasts, a contention that our project proposes to assess. A second observation we made was that Tph1+/- mice born from Tph1-/- mothers have a significantly lower bone mass at 3 months of age than Tph1+/- mice born from wild-type mothers. These data suggest that maternal serotonin and/or melatonin could be determinants of peak bone mass in the adult offspring. Serotonin does not cross the placenta but Tph1 expression in this tissue causes its release in fetal blood. Likewise, maternal melatonin reaches the fetal circulation. We therefore propose to evaluate whether maternally-produced melatonin and/or serotonin are required for proper bone mass acquisition and homeostasis in the offspring.
Our specific aims are: 1) To assess through genetic means the role of melatonin produced by the pineal gland on bone biology. 2) To identify the receptor(s) and signaling pathway(s) mediating melatonin function(s) in osteoblasts in vivo. 3) To define the cellular and molecular bases of the influence exerted by maternal Tph1 expression on bone mass accrual in the offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG032959-10
Application #
9694578
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
De Vadder, Filipe; Grasset, Estelle; Mannerås Holm, Louise et al. (2018) Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci U S A 115:6458-6463
Obri, Arnaud; Khrimian, Lori; Karsenty, Gerard et al. (2018) Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nat Rev Endocrinol 14:174-182
Khrimian, Lori; Obri, Arnaud; Karsenty, Gerard (2017) Modulation of cognition and anxiety-like behavior by bone remodeling. Mol Metab 6:1610-1615
Khrimian, Lori; Obri, Arnaud; Ramos-Brossier, Mariana et al. (2017) Gpr158 mediates osteocalcin's regulation of cognition. J Exp Med 214:2859-2873
Mosialou, Ioanna; Shikhel, Steven; Liu, Jian-Min et al. (2017) MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543:385-390
Mera, Paula; Laue, Kathrin; Wei, Jianwen et al. (2016) Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab 5:1042-7
Galán-Díez, Marta; Isa, Adiba; Ponzetti, Marco et al. (2016) Normal hematopoiesis and lack of ?-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain-of-function mutations. Biochim Biophys Acta 1863:490-498
Ortuño, María José; Robinson, Samuel T; Subramanyam, Prakash et al. (2016) Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect. Nat Med 22:1170-1179
Kode, A; Mosialou, I; Manavalan, S J et al. (2016) FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30:1-13
Shimazu, Junko; Wei, Jianwen; Karsenty, Gerard (2016) Smurf1 Inhibits Osteoblast Differentiation, Bone Formation, and Glucose Homeostasis through Serine 148. Cell Rep 15:27-35

Showing the most recent 10 out of 34 publications