Gut drives bone makeovers

The signals that tell your skeleton to lay down new bone come from an unlikely source -- your gut, according to a study published today (Nov. 26) in Cell. "This study revolutionizes how we think about the skeleton," linkurl:Cliff Rosen,;http://www.mmcri.org/cctr/rosen.html a bone biologist from Maine Medical Center Research Institute who was not involved in the research, told The Scientist. "We, as bone [researchers], thought of the skeleton as functioning independent of everything else," Rosen said. This group "asked the question, 'could there be other regulators outside the skeleton that are regulating bone?' and found the answer to be 'yes.'" The skeleton undergoes constant linkurl:remodeling;http://www.the-scientist.com/news/display/53475/ and through the steady process of absorbing and laying down new bone, renews itself roughly every 10 years, Rosen said. That remodeling process is thrown off linkurl:balance;http://www.the-scientist.com/article/display/13675/ in certain bone diseases or simply with age, resulting in low bone mass, or osteoporosis. linkurl:Earlier studies;http://www.ncbi.nlm.nih.gov/pubmed/11719191 in patients with two types of rare bone diseases that cause high and low bone density, respectively, identified a hormone called LDL-receptor related protein 5 (Lrp5) as a key player in bone remodeling. This finding sparked enthusiasm among bone researchers hungry to identify a drug that could repair bone damage, Columbia University molecular geneticist Patricia Ducy, coauthor on the Cell study, told The Scientist. The majority of drugs on the market arrest bone loss, but fail to promote bone repair, she said. linkurl:Gerard Karsenty,;http://cpmcnet.columbia.edu/dept/genetics/faculties/Karsenty.html a geneticist also at Columbia and senior author on the Cell paper, was studying Lrp5 knockouts, which develop osteoporosis. Microarray studies of gene expression in bone cells identified a surprisingly high expression of tryptophan hydroxylase 1 (Tph1), an enzyme that regulates serotonin production in the gut, in knockouts compared to normal mice. Researchers have long known the duodenum, a region of the small intestine, produces the majority of serotonin found in the body, but unlike serotonin's well-understood role in the brain, its role in the body was less clear. However, there have been linkurl:reports;http://archinte.ama-assn.org/cgi/content/abstract/167/2/188 that some patients taking selective serotonin reuptake inhibitors (SSRI), which increase serotonin levels throughout the body, experience decreases in bone mass. The microarray findings led researchers to take a closer look at the duodenum cells of their Lrp5-deficient mice, Ducy said, where they discovered Tph1 was expressed 15,000-times higher than levels seen in normal mice, suggesting the gut was somehow involved in controlling bone remodeling. To confirm the link between the gut and bone formation, the researchers created transgenics with cell-specific Lrp5-deficiency in the duodenum and bone cells. When Lrp5 was absent in gut cells, circulating serotonin levels were 5- to 8-fold higher than in normal mice and bone mass decreased whereas mice with Lrp5 deficiency in bone cells remained normal. Conversely, blocking Tph1 in the gut cells, but not bone cells, of Lrp5-deficient mice led to increased bone mass. Normal mice experience osteoporosis following menopause, but the Tph1 deficiency was enough to protect the knockouts from osteoporosis. In further gene deletion experiments, they identified the receptor on bone cells through which serotonin signals. "Lrp5 and Tph1 are two partners in crime," Ducy said, with Lrp5 inhibiting expression of Tph1 and serotonin. "In the absence of Lrp5, you have more Tph1 and serotonin" expressed in the gut. The group also obtained serum from patients with the high and low bone density diseases linked to Lrp5, Karsenty said. Patients with the low bone density disease had raised serotonin levels, and those with high bone mass disease had suppressed serotonin levels, suggesting "this is more than just a mouse study," he said. Serotonin is "a schizophrenic molecule, working differently in the body depending on whether it's upstairs or downstairs," Ducy said. "What's important is serotonin does not cross blood-brain barrier," she added, making it an attractive drug target for treating osteoporosis -- inhibiting Tph1 in the body wouldn't affect serotonin levels in the brain.

Gut drives bone makeovers

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