Posted by Larry Hoover on December 6, 2008, at 9:05:43
There was a paper published late last month that really got me thinking. For the first time, it's been shown that processes occurring in the gut can have a profound effect on bone formation by regulating the number, and thus the activity of, osteoblasts. Bone is constantly being formed and destroyed by cells called osteoblasts and osteoclasts, respectively. Assuming that the body has the mineral resources to allow them to function properly, it's the balance between the activity of the two that determines bone density.
I'll post the abstract to the paper, and an article about the paper at the bottom. I'll try and give the gist of it, and discuss why I think it's an important finding.
The amino acid tryptophan, from dietary protein, is absorbed in the duodenum. Cells lining the duodenum express the enzyme tryptophan hydroxylase (TRP), which converts tryptophan into 5-hydroxy-tryptophan (5-HTP, also available as a supplement). It turns out that it's the activity of this enzyme in the duodenum that largely determines blood serotonin concentration, as 5-HTP is rapidly converted to serotonin by an enzyme that is common-place throughout the body. It had been thought that it's the liver that regulated this, but it turns out it's the gut.
Serotonin circulating in the blood regulates the proliferation of osteoblasts. Low levels of serotonin lead to high proliferation rates of osteoblasts, and in turn, high bone formation rates. In contrast, high serotonin levels suppress osteoblast proliferation. This may explain the finding that some antidepressants are associated with loss of bone density, because they can shift a vulnerable person's bone synthesis balance into the negative range.
In the referenced paper, the researchers tweaked the process at various points (in mice), and found they could control bone density quite predictably. What this suggests is that entirely new therapies for osteoporosis are possible. Rather than merely slowing bone loss, it might easily be reverted.
The biochemical regulatory sequence allows intervention at four points, as I see it.
First, gut tryprophan hydroxylase activity is regulated by an LDL (low-density lipoprotein) receptor. High activity at that receptor suppresses TRP. I'm not sure that messing around at that level would be clear-cut, as we're still very much in the dark with respect to cholesterol regulation.
Second, the peripheral tryptophan hydroxylase enzyme (TRP type 1) could be inhibited. That was tried in the mice, and it worked. Bone density increased, even in mice genetically predisposed to low bone density. Because there is a completely separate enzyme behind the blood brain barrier, a peripheral inhibitor would not affect brain serotonin synthesis.
Third, you could inhibit the peripheral aromatic decarboxylase enzyme. Carbidopa is one such drug, and it is given with the dopamine precursor L-DOPA in treatments for Parkinson's disease, to prevent dopamine forming outside the brain. The very same enzyme converts 5-HTP to serotonin, so we already have one intervention available. I've never heard of carbidopa being used to treat osteoporosis, but hey! Who knows. As an aside, I earlier mentioned that the gut creates 5-HTP from tryptophan, and that's what leads to high blood serotonin and bone loss. That would mean that 5-HTP supplements would predispose to osteoporosis, also. I'm thinking that 5-HTP would best be taken with carbidopa, if that's someone's antidepressant strategy.
Fourth, and perhaps most promising, as it acts directly at the point of regulation of osteoblast proliferation, is that they could block the specific serotonin receptor involved (called Htr1b). They were able to do that in the mice, and osteoblast activity was up-regulated, leading to higher bone density.
So, promising new leads, methinks. I'd expect human trials before too long, as none of it is too far beyond our current capabilities.
Here are the abstract, and the article discussing the research. N.b., the article has an error in the second last paragraph. I believe it should say "lower" rather than "higher".
Regards,
Larhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=1904174
Cell. 2008 Nov 28;135(5):825-37.
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.
Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G.
Department of Genetics and Development, Columbia University, New York, NY 10032, USA.Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.
http://www.medpagetoday.com/Endocrinology/Osteoporosis/11923
Serotonin in Gut Linked to Bone Formation
NEW YORK, Nov. 26 -- That Thanksgiving turkey may be bad for your bones. That's one of the implications of a study that -- for the first time -- links the gut to bone formation, according to Gerard Karsenty, M.D., Ph.D., of the Columbia University College of Physicians and Surgeons, and colleagues. The research, conducted mainly in mice, links serotonin produced in the duodenum to the proliferation of osteoblasts, the cells that create new bone, Dr. Karsenty and colleagues reported in the Nov. 26 issue of Cell. "This is totally new," Dr. Karsenty said. "We had no clue that the gut had control over bone, and in such a powerful manner."
The findings open up the possibility of controlling such diseases as osteoporosis either by a diet low in tryptophan -- the raw material for serotonin synthesis -- or by inhibiting the serotonin-osteoblast interaction with medications.If diet turns out to be a possible approach, the turkey may have to go --it's one of the best dietary sources of tryptophan.
Until these experiments, Dr. Karsenty said, the function of gut-associated serotonin was not known.
"The findings demonstrate without a doubt that serotonin from the gut is acting as a hormone to regulate bone mass," he said.
But the discovery was accidental. The researchers were investigating the role of a protein known as LDL-receptor related protein 5 (or LRP5), which causes osteoporosis pseudoglioma when mutations lead to a loss of function.
Other mutations in LPR5, which presumably cause overactivity (gain-of-function mutations), are associated with diseases characterized by high bone mass, the researchers noted.
The first hint of a link to serotonin came when they noted that a key player in the molecule's synthesis -- the enzyme tryptophan hydroxylase 1 (or Tph1) -- is highly overexpressed in the duodenum of mice lacking LPR5.
Tph1 is the enzyme that limits the rate at which serotonin is produced in the gut. Indeed, 95% of the body's serotonin is produced in the gut; because it does not cross the blood-brain barrier, a second enzyme, Tph2, is responsible for serotonin in the brain.
In mice lacking LRP5, levels of Tph1 are normal at birth and begin to show significant increases (at P<0.01) compared to wild-type animals at two weeks of age.
The low bone mass syndrome in those animals begins to appear two weeks later.
In parallel, serum serotonin levels also increase as the animals age, the researchers noted.
Interestingly, the researchers noted, in an earlier case-control analysis of three patients with osteoporosis pseudoglioma, serum serotonin levels were four- to five-fold higher than in six age-matched controls.
In an in vitro experiment, the researchers found that serotonin inhibits osteoblast proliferation, so they fed mice a diet with 75% less tryptophan than normal.
In mice lacking LPR5 -- and therefore prone to low bone mass -- the diet decreased circulating serotonin levels eight- to 10-fold (without affecting serotonin in the brain) and normalized both bone mass and bone formation parameters.
A similar experiment, using a compound that blocks serotonin synthesis, had nearly identical results.
The researchers also found that only one of the three serotonin receptors on osteoblasts (a molecule dubbed Htr1b) is involved in the process -- blocking the other two had no effect on bone mass, while blocking Htr1b increased the number of osteoblasts, bone mass, and the bone formation rate.
In a final experiment, they engineered mice lacking the gene for Tph1 and removed the ovaries from female animals at six weeks of age. At three months, bone resorption had increased, but the animals had not developed low bone mass because they were still building new bone.
That experiment in particular holds out clinical promise, Dr. Karsenty said. "Osteoporosis is often diagnosed when the damage to bone is already significant and fracture risk is already too high," he said. "We need something to build bone, not just prevent or repair its loss."
The cells that produce serotonin come in contact with drugs that pass through the gastrointestinal tract, he said, so reducing gut-associated serotonin should be relatively simple to achieve with a drug.
Dr. Karsenty said he thinks there should be few side effects of such a drug, since patients with high bone mass often have circulating serotonin levels as much as 50% higher than normal without other symptoms.
He added that he sees no theoretical obstacles to finding medications that modulate the body's serotonin. "If we can do it in the brain," he said, "we can do it in the body."
poster:Larry Hoover
thread:866984
URL: http://www.dr-bob.org/babble/20081204/msgs/866984.html