Constitutively elevated blood serotonin is associated with bone loss and type 2 diabetes in rats

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) 2 D 3 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.

Autologous blood coagulum is a physiological carrier for BMP6 to induce new bone formation and promote posterolateral lumbar spine fusion in rabbits

“…Concurrent dataset analysis of the site of implantation was analysed by CTAn (Sky Scan) software. The new bone formation and trabecular bone parameters were depicted throughout the whole area of newly formed bone, as previously described (Erjavec et al, ; Grgurevic et al, ).…”

Recombinant Human Bone Morphogenetic Protein 6 Delivered Within Autologous Blood Coagulum Restores Critical Size Segmental Defects of Ulna in Rabbits

“…In subcutaneous rat assay, bone formation was scanned in vivo after 14 days using SkyScan 1076 micro‐CT device (SkyScan/Bruker) at 18 μm resolution, as previously described . Scanning parameters were 50 kV/200 μA, 0.5 mm aluminum filter, 0.8° rotational shift throughout the 198° and frame averaging value set at 2.…”

Constitutive Serotonin Tone Modulates Molecular and Behavioral Response to Chronic Fluoxetine Treatment: A Study on Genetic Rat Model

“…Thus, animals from the high-5HT subline, compared to the low-5HT subline, show higher 5HT turnover and 3 H-citalopram binding in several brain regions as well as higher KCl-and citalopram-induced elevation in extracellular 5HT in hippocampal tissue (14). A number of functional traits modulated by central and/or peripheral 5HT signaling differ between 5HT sublines (15)(16)(17)(18)(19)(20) and the pattern of changes is consistent with relatively higher whole-body 5HT activity in high-5HT as compared to low-5HT animals.…”