Decreased osteoclastogenesis in serotonin-deficient mice

Abstract

Peripheral serotonin, synthesized by tryptophan hydroxylase-1 (TPH 1 ), has been shown to play a key role in several physiological functions. Recently, controversy has emerged about whether peripheral serotonin has any effect on bone density and remodeling. We therefore decided to investigate in detail bone remodeling in growing and mature TPH 1 knockout mice (TPH 1 −/−). Bone resorption in TPH 1 −/− mice, as assessed by biochemical markers and bone histomorphometry, was markedly decreased at both ages. Using bone marrow transplantation, we present evidence that the decrease in bone resorption in TPH 1 −/− mice is cell-autonomous. Cultures from TPH 1 −/− in the presence of macrophage colony-stimulating factor and receptor activator for NF-KB ligand (RANKL) displayed fewer osteoclasts, and the decreased differentiation could be rescued by adding serotonin. Our data also provide evidence that in the presence of RANKL, osteoclast precursors express TPH 1 and synthesize serotonin. Furthermore, pharmacological inhibition of serotonin receptor 1B with SB224289, and of receptor 2A with ketanserin, also reduced the number of osteoclasts. Our findings reveal that serotonin has an important local action in bone, as it can amplify the effect of RANKL on osteoclastogenesis.neuromediator | osteopetrosis B one remodeling is a highly integrated process that continuously renews mineralized tissue throughout the skeleton to assure harmonious growth, maintenance, and repair throughout the lifespan of the individual. It couples the resorption of mineralized bone by osteoclasts and bone formation by osteoblasts. Osteoblasts originate from mesenchymal stem cells (1), and osteoclasts are multinucleated cells derived from a hematopoietic precursor of the monocyte macrophage lineage (2). Dysregulation of osteoclast function or differentiation results in an osteopetrotic phenotype, with a marked increase in bone density. In contrast, increased bone resorption is associated with bone loss in diseases such as osteoporosis, arthritis, and metastatic bone lesions. Molecular communication between osteoblasts and osteoclasts is required to regulate the commitment, proliferation, and differentiation of bone cell precursors. The main osteoclastogenic signals are the receptor activator for NF-KB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), both of which are cytokines secreted by osteoblasts (3).Serotonin, or 5-hydroxytryptamine (5-HT), mediates a wide range of central functions, such as mood, behavior, sleep, blood pressure, and thermoregulation (4). Peripherally, serotonin is involved mainly in the regulation of vascular and heart functions (5, 6) and in gastrointestinal mobility (7). The diverse actions of 5-HT result from the presence of multiple 5-HT receptors (5-HTRs). These various different receptors have been divided into seven classes (5-HT 1 R to 5-HT 7 R) (8). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. There are two isoforms of this enzyme: TPH 2 is mainly expressed in brain, and...

Life without Peripheral Serotonin: Insights from Tryptophan Hydroxylase 1 Knockout Mice Reveal the Existence of Paracrine/Autocrine Serotonergic Networks

“…Recently, Chabbi-Achengli et al, using mice with a constitutive Tph1 gene inactivation, provided evidence that a local serotoninergic system expressed in osteoclasts regulates bone remodeling. 68 The authors observed an elevated bone density in young Tph1−/− animals that returns to normal at maturity 68 in agreement with the above-mentioned report of Cui et al studying mice with a global Tph1 KO. They also showed that Tph1-derived 5-HT produced by osteoclasts in the bone could act locally on both osteoclasts and osteoblasts.…”

“…They also showed that Tph1-derived 5-HT produced by osteoclasts in the bone could act locally on both osteoclasts and osteoblasts. 68 In vivo experiments demonstrated that WT bone marrow cells transplanted in Tph1−/− mice retard the deficit in bone resorption, suggesting that an intrinsic osteoclast defect is responsible for the abnormal bone phenotype.…”

Differentially expressed genes in autosomal dominant osteopetrosis type II osteoclasts reveal known and novel pathways for osteoclast biology

“…53 We had observed previously that osteoclasts can synthesize serotonin from tryptophan, and this triggers osteoclast differentiation as they express tryptophan hydroxylase 1. 54 It is therefore possible that WARS is related to the osteoclast biology, but we could not confirm it in the transfection experiment. WARS had not previously been observed in osteoclasts, and its function in this cell is unknown.…”

Increasing serotonin concentrations alter calcium and energy metabolism in dairy cows

“…Serotonin is directly involved in bone metabolism via the decreasing of bone formation and the stimulation of bone resorption (Ducy 2011). In fact, serotonin-deficient male mice exhibit reduced bone resorption (Chabbi-Achengli et al 2012). Therefore, it is possible that serotonin impacts bone directly and indirectly by stimulating PTHrP synthesis by the mammary gland during lactation to induce bone resorption (Horseman & Hernandez 2014).…”