Gut-derived serotonin regulated bone formation

Serotonin produced in the gut acted as a powerful regulator of bone formation in vivo and demonstrated the existence of an entero-skeletal endocrine axis, according to recent study results published in Cell.

“We had no clue the gut had control over bone and in such a powerful manner,” Gerard Karsenty, MD, PhD, professor and chair of genetics & development at Columbia University in New York, said in a press release.

Several years ago, two human disorders, osteoporosis pseudoglioma, which develops in young children and is characterized by catastrophic loss of bone, and high bone mass syndrome (in which affected heterozygous patients develop a high bone mass) were identified with mutations in a cell surface molecule — LRP5, according to Patricia Ducy, PhD, assistant professor of pathology at Columbia University.

The researchers compared the transcriptome of wild type with LRP5–deficient mice, searching for the mode of action of LRP5. They determined that the most differently expressed gene was TPH1, a gene that encodes a key enzyme in the biosynthesis of peripheral serotonin from tryptophan, according to Ducy.

“After this initial finding, we continued using mouse genetics to demonstrate that it was the LRP5 expressed in gut cells, not in bone cells, that was controlling bone mass and that its role was to regulate TPH1 expression and thereby serotonin synthesis in the gut,” she told Endocrine Today.

“We also identified which serotonin receptors mediate this hormone action on osteoblasts, the bone-forming cells,” she said.

Results showed that decreasing serotonin blood levels normalized bone formation and bone mass in LRP5–deficient mice, and gut- but not bone-specific LRP5 inactivation decreased bone formation, according to a press release. Gut-specific activation of LRP5, or inactivation of TPH1, increased bone mass and prevented bone loss in mice that had their ovaries removed.

“[The findings of this study uncover] an unanticipated molecular mechanism accounting for the LRP5 regulation of bone formation; our findings shift the emphasis from a paracrine to an endocrine regulation of bone mass and from bone cells to enterochromaffin cells of the gut,” the researchers wrote.

Possible osteoporosis therapy

Although the findings were in mice, they have direct application to understanding bone remodeling in people, according to Karsenty.

“This is not a mouse story,” he said in a press release. “From the beginning, it was a human story that we have now worked out in the mouse.”

Ducy said that when the researchers evaluated patients affected by osteoporosis pseudoglioma and high bone mass syndrome disorders, they showed patients had abnormal blood serotonin levels. In the mice, the researchers showed that the absence of TPH1 (the absence of serotonin) could protect the mice from developing osteoporosis after ovariectomy, according to Ducy.

“This result and the fact that serotonin appears to play the same role in mice and human beings raise the prospect that developing specific inhibitors of serotonin synthesis in the gut could be a novel approach toward an anabolic treatment of osteoporosis,” she said.

Further, these findings also provide an explanation for another observation: patients with autism who have high blood serotonin levels often have osteoporosis. Those taking SSRIs chronically can also have reduced bone mass. However, the researchers noted that it is too soon to say whether this possible new connection between gut serotonin and bone may or may not explain that adverse event of the drugs. – by Christen Haigh

Cell. 2008;135:825-837.

Mutations of LRP5 have been known for several years to cause alterations of bone mass. Loss of function mutations cause the osteoporosis pseudoglioma syndrome, while gain of function mutations cause high bone mass. Until now, paracrine signaling via the Wnt pathway has generally been believed to be the mechanism underlying the bone manifestations of these mutations. In this study, Yadav and colleagues reported an elegant and extensive series of experiments that demonstrate that serotonin produced in duodenal enterochromaffin cells acts in an endocrine fashion via Htr1b serotonin receptors and the transcription factor CREB to suppress proliferation of osteoblasts.

To reach this understanding, the authors undertook a series of genetic experiments in mice that exploit the ability to introduce mutations in a tissue-specific manner. Thus, restricting loss of function mutations to the enterochromaffin cells produces the expected low bone mass phenotype while restricting them to osteoblasts has no discernable effect on bone mass, as assessed in vertebral trabecular bone by histomorphometry. The alterations in circulating serotonin levels demonstrated in the mice were also observed in human patients with LRP5 mutations. By reproducing the bone effects of the mutations by using other means to alter circulating serotonin levels and by showing that the skeletal effects depend on a specific class of serotonin receptors, they have proven the existence of a novel endocrine axis between the gut and bone. Their discovery represents a major conceptual advance and will have far-reaching implications on our understanding of metabolic bone disease.

For example, the authors showed that limiting gut serotonin production prevents bone loss in ovariectomized mice. Therefore, serotonin production and binding to the Htr1b receptor become potential targets for drugs to prevent fracture.

This is by no means the last word on the mechanisms by which LRP5 specifically, or Wnt signaling more generally, affects the skeleton. There is a substantial body of evidence that implicates Wnt signaling in skeletal adaptation to the mechanical loading environment, and this aspect of the biology has not been addressed by the new experiments. Moreover, the authors’ failure to detect direct Wnt signaling in bone may also be due to limitation of the osteoblast-specific mutations to cells that have already passed a critical point in differentiation.

That important questions remain unanswered is not a criticism of Yadav and colleagues’ work. Good science generates answers to questions, but it also generates new questions that must be answered. This is work that has the potential to fundamentally change our understanding of bone mass homeostasis and to be translated to clinical practice relatively quickly.

– Robert D. Blank, MD, PHD

Endocrine Today Editorial Board member