Bone density may be determined in the gut

Columbia, November 26: Researchers have produced new evidence that our guts play a surprisingly important role in remodeling our bones.

Bone growth is controlled in the gut through serotonin, a naturally present chemical used by the brain to influence mood appetite and sleep.

R Gerard Karsenty, chairman of the Department of Genetics and Development at the Columbia University College of Physicians and Surgeons, said “This is totally new. We had no clue that the gut had control over bone and in such a powerful manner.”

Researchers believe that 95 percent of the body serotonin is produced by duodenum, a part of the gastrointestinal tract involved in digestion. The remaining 5 percent of the serotonin is produced in the brain.

The link between serotonin and bone density comes from studying Lrp5, a gene that regulates bone formation. Dr Karsenty and his team found that by turning on and off the production of the chemical in the gut they could control bone formation. They discovered that serotonin tells cells in the skeleton to slow down the production of new bones. To study how Lrp5 might regulate bone density in humans, the team turned to mice.

Using transgenic mice, the researchers showed inactivating Lrp5 caused severe osteoporoses while over-activating Lrp5 led to higher bone mass. They also learned that Lrp5 blocks conversion of aminoacid tryptophan to serotonin. In other words the density of the bones of the mice could be changed by adjusting the amount of tryptophan in their diet.

Although the findings were made on mice, Karsenty says they help to understand bone modeling in humans “This is not a mouse story. From the beginning it was a human story that we have worked out in the mouse.”

The research, though basic, suggests new avenues of osteoporoses in humans. Bjorn Oslen, a Harvard College biologist, feels “It’s what you call a landmark study. It opens new doors.”

Dr Karsenty further elaborated “The proof of the principal paper shows to our amazement that bone formation is regulated to a significant extent by the gut. Through our observations of two rare and severe forms of osteoporoses, one that causes drastic bone loss and one that causes extremely high bone mass, we were able to see clearly what happens with over production or under production of serotonin. Our hope is that this novel discovery will inform the development of new therapies for the millions of people with osteoporoses.”

The link between serotonin and bones began with reports of a rare and inherited disease causing fragile bones and blindness. Children inflicted with the ailment had such weak bones that they required wheel chairs for mobility.

Looking at patients with dense bone mutation, Dr Karsenty discovered they had low levels of serotonin in their blood. Osteoporoses patients tend to have normal serotonin levels as the problem involves not impaired bone formation but accelerated bone loss.
Bones are not inert, they constantly under go renovation. Some cells remove old material and there are others responsible for creating new bone. In humans after 20 years the balance between bone formation and its breakdown tips, leading to a decline in bone mass. This shifting causes osteoporoses.

This discovery that intestinal serotonin is central to bone formation is likely to challenge the belief that the majority of hormonesdefine that control bone mass had been identified.

Dr Karsenty clarified, “As an endocrinologist, I have spent a large part of my career inspecting the inter play between energy metabolism and bone mass. This demonstration of the vital function of bone proliferation stemming from the gut gives pause to those in my field who perhaps have not given the gut its due examination or the credit it deserves for how much it controls the body and that includes me.”

Nearly 10 million Americans over the age of fifty are affected by osteoporoses. It results in making bones fragile as well as bone loss. Most drugs for this problem do not generate new bone but prevent the break down of old bone. Only one drug currently in the market can generate new bone. It is parathyroid hormone given by injection. The drug is expensive costing 6700 dollars and is recommended for short use only.

Dr Karsenty felt, “the lack of bone promoting drugs is a major concern because osteoporoses is often diagnosed when the damage to bone is already significant and fracture risk is already too high. We need something to build bone not just preserve or repair its loss.”

The finding that serotonin may regulate bone mass is a fabulous discovery. It could have enormous implications because there is a need for osteoporoses treatment that actually builds bones. Mathew Warman, a researcher studying bones at Children’s Hospital, Boston said “Although the role of the gut formation is potentially paradigm shifting, like any paradigm it requires additional confirmation.”

The paper was published in the journal Cell.