Dietary tryptophan manipulation reveals a central role for serotonin in the anabolic response of appendicular skeleton t
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ORIGINAL ARTICLE
Dietary tryptophan manipulation reveals a central role for serotonin in the anabolic response of appendicular skeleton to physical activity in rats Valeria Sibilia • Francesca Pagani • Elisa Dieci • Emanuela Mrak • Marcella Marchese Guido Zarattini • Francesca Guidobono
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Received: 30 January 2013 / Accepted: 13 April 2013 Springer Science+Business Media New York 2013
Abstract Several studies support a serotonin role in the physiological control of bone mass. However, whether serotonin (5-HT) is involved in bone loss due to reduced mechanical stress or unloading is unknown. We investigated the effects of reduced 5-HT tone, induced by tryptophan-free diet, in movement-restraint osteopenia induced by housing mature rats, acclimatised in single cages with a floor area of 1,500 cm2, in smaller size single cages where their motor activity was reduced. Tryptophan-deficiency significantly worsened movement-restraint-induced bone loss in both femoral metaphysis and diaphysis (DXA analysis) but not at lumbar vertebrae and impaired the mechanical properties of the femur by significantly reducing both cortical thickness and strength strain index (pQCT analysis). Such effects resulted from an impairment of bone turnover with bone resorption exceeding bone formation. Tryptophan-supplemented diet reversed the worsening effects of tryptophan-deficiency on movementrestraint osteopenia. The improvements of both bone mass and strength were associated with an increase of serum osteocalcin and IGF-I, markers of osteoblast activity. In vitro studies in primary cultures of rat osteoblasts suggest that the anabolic action of 5-HT involves the activation of the Wnt/b-catenin pathway. Serotonin significantly increased the cytoplasmatic b-catenin protein levels by the inhibition of the enzyme glycogen synthase kinase-3b, that V. Sibilia (&) F. Pagani E. Dieci E. Mrak F. Guidobono Department of Medical Biotechnology and Translational Medicine, Medical Pharmacology Unit, Universita` degli Studi di Milano, Via Vanvitelli, 32, Milan 20129, Italy e-mail: [email protected] M. Marchese G. Zarattini Department of Ortopaedics and Traumatology, Universita` degli Studi di Brescia, Brescia, Italy
by phosphorylating b-catenin promotes its degradation. Our data support a role for 5-HT in the anabolic response of the appendicular skeleton to mechanical loading. We suggest that serotonin might stimulate canonical Wnt/bcatenin-dependent bone formation to occur. Keywords Tryptophan Serotonin depletion Physical exercise Bone metabolism Wnt pathway
Introduction Several recent in vivo and in vitro studies have demonstrated that serotonin (5-HT) may act as a signalling molecule in bone [1, 2]. In line with the wide range of central and peripheral functions exerted by 5-HT, the action of 5-HT on bone involves a complex action through its receptors and specialized 5-HT membrane transporters (5HTT) for the uptake of released 5-HT. Osteoblasts, osteocytes, and osteoclasts express several 5-HT receptors (5-HTR) and po
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