Measurement of Plasma, Serum, and Platelet Serotonin in Individuals With High Bone Mass and Mutations in LRP5

Abstract

It has recently been suggested that the low-density lipoprotein receptor-related protein 5 (LRP5) regulates bone mass by suppressing secretion of serotonin from duodenal enterochromaffin cells. In mice with targeted expression of a high bone mass-causing (HBM-causing) LRP5 mutation and in humans with HBM LRP5 mutations, circulating serotonin levels have been reported to be lower than in controls while individuals with loss-of-function mutations in LRP5 have high blood serotonin. In contrast, others have reported that conditionally activating a knock-in allele of an HBM-causing LRP5 mutation in several tissues, or genetic deletion of LRP5 in mice has no effect on serum serotonin levels. To further explore the possible association between HBM-causing LRP5 mutations and circulating serotonin, levels of the hormone were measured in the platelet poor plasma (PPP), serum, and platelet pellet (PP) of 16 affected individuals from 2 kindreds with HBM-causing LRP5 mutations (G171V and N198S) and 16 age-matched controls. When analyzed by HPLC, there were no differences in levels of serotonin in PPP and PP between affected individuals and age-matched controls. Similarly, when analyzed by ELISA, there were no differences in PPP or PP between these two groups. By ELISA, serum levels of serotonin were higher in the affected individuals when compared to age-matched controls. A subgroup analysis of only the G171V subjects (n=14) demonstrated that there were no differences in PPP and PP serotonin between affected individuals and controls when analyzed by HPLC. PP serotonin was lower in the affected individuals when measured by ELISA but serum serotonin levels were not different. We conclude that there is no change in PPP serotonin in individuals with HBM-causing mutations in LRP5.

Atypical Femoral Fracture in Osteoporosis Pseudoglioma Syndrome Associated with Two Novel Compound Heterozygous Mutations in LRP5

“…It has been suggested that LRP5 regulates bone mass through duodenal serotonin synthesis, (61) although not all subsequent analyses have supported this finding. (62,63) Furthermore, serotonin levels in high bone mass, due to activating LRP5 mutations, have been reported to be normal (64) ; whether the same holds for OPPG remains to be determined.…”

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

“…Low plasma 5HT was reported also in patients with high-bone-mass phenotype (HBM) owing to Lrp5-T2531 mutation [9], however, a subsequent study by other authors failed to find any correlation between 5HT and bone mass in HBM population [14]. At this point it is not clear whether 5HT synthesized by the osteoclastic cells or in the gut is playing a role in our model system.…”

“…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]. There is controversy regarding the role of LRP5 in regulating peripheral serotonin levels and influence of peripheral serotonin on bone homeostasis [8][9][10][11][12][13][14][15][16]. Further, use of antidepressant medications, which act on serotonin system, has been shown to have impact on decreasing BMD and to increase risk for osteoporosis [17].…”

WNT signaling in bone development and homeostasis

“…Increased levels of serum serotonin then function via binding to the HTR1B receptor to inhibit osteoblast proliferation. However, data from several other laboratories is not consistent with this model . The reasons for these discrepancies are currently unclear.…”