Abstract
Reduced peripheral serotonin (5HT) in mice lacking tryptophan hydroxylase (TPH1), the rate limiting enzyme for 5HT synthesis, was reported to be anabolic to the skeleton. However, in other studies TPH1 deletion either had no bone effect or an age dependent inhibition of osteoclastic bone resorption. The role of 5HT in bone therefore remains poorly understood. To address this issue, we used selective breeding to create rat sublines with constitutively high (high-5HT) and low (low-5HT) platelet 5HT level (PSL) and platelet 5HT uptake (PSU). High-5HT rats had decreased bone volume due to increased bone turnover characterized by increased bone formation and mineral apposition rate, increased osteoclast number and serum C-telopeptide level. Daily oral administration of the TPH1 inhibitor (LX1032) for 6 weeks reduced PSL and increased the trabecular bone volume and trabecular number of the spine and femur in high-5HT rats. High-5HT animals also developed a type 2 diabetes (T2D) phenotype with increased: plasma insulin, glucose, hemoglobin A1c, body weight, visceral fat, β-cell pancreatic islets size, serum cholesterol, and decreased muscle strength. Serum calcium accretion mediated by parathyroid hormone slightly increased, whereas treatment with 1,25(OH)2D3 decreased PSL. Insulin reduction was paralleled by a drop in PSL in high-5HT rats. In vitro, insulin and 5HT synergistically up-regulated osteoblast differentiation isolated from high-5HT rats, whereas TPH1 inhibition decreased the number of bone marrow-derived osteoclasts. These results suggest that constitutively elevated PSL is associated with bone loss and T2D via a homeostatic interplay between the peripheral 5HT, bone and insulin.
Highlights
Serotonin (5-hydroxytryptamine, 5HT) has multiple functions in peripheral organs acting via 15 transmembrane receptors
Bidirectional genetic selection of rats toward extreme activities of platelet 5HTT through successive generations, resulted in divergence into two discrete sublines with lifelong hyper- or hyposerotonemia as well as constitutional hyper- or hypoactivity of the serotonergic system in general [18]. We hypothesized that these constitutive differences in serotonergic phenotype might affect skeletal tissue. In these studies we demonstrated that rats with high platelet serotonin level (PSL) had an increased bone turnover with subsequent bone loss and developed a type 2 diabetes (T2D) phenotype
Our model is generated by selection for naturally occuring extreme PSL values and reflects the physiological conditions more closely than similar models generated by genetic manipulation
Summary
Serotonin (5-hydroxytryptamine, 5HT) has multiple functions in peripheral organs acting via 15 transmembrane receptors. It was suggested that gut-derived 5HT suppresses osteoblast proliferation and that its synthesis is regulated via the low-density lipoprotein receptor-related protein 5 (LRP5) in the gut, but in osteoblasts 5HT acts in a non-LRP5 dependent manner to inhibit bone formation [1]. An association among LRP5 deficiency, circulating 5HT and bone loss has not been reproduced in mice with osteocyte-specific expression of inducible Lrp mutations that cause high and low bone mass phenotypes in humans [3]. De Vernejoul and colleagues revisited the bone phenotype in mice with genetic deletion of peripheral 5HT-synthesizing enzyme tryptophan hydroxylase-1 (TPH1-/-) and showed that osteoclasts synthesize 5HT which acts to induce osteoclast precursor differentiation in a local micro-serotoninergic system via a mechanism of RANKL-induced osteoclast formation [7]
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