Bone remodeling protein works indirectly through gut

May 12, 2009

The protein Lrp5, long known to play a critical role in bone remodeling, appears to exert its effects through the gut, not directly through the bone, as previously thought, according to preclinical research published in Cell. The findings could suggest new therapeutic approaches to increase bone mass in older adults and others with osteoporosis.

In bone remodeling, old bone is resorbed by specialized cells, called osteoclasts, and new bone is formed by other specialized cells, called osteoblasts. Lrp5 (low-density lipoprotein receptor-related protein 5) is an important regulator in the underlying molecular process. A decrease in its function can lead to osteoporosis, while overproduction results in high bone mass syndromes in humans.

Scientists have long believed that Lrp5 controls bone mass through signaling in the Wnt pathway in bone osteoblasts. However, NIH-supported researchers at Columbia University found that Lrp5 works indirectly through the gut. In a study in mice, they found that Lrp5 inhibits expression of the gene Tph1, which encodes an enzyme that, in turn, helps synthesize serotonin in the duodenum. The resulting decrease in serotonin production was associated with increased bone mass in mice. Conversely, mice deficient in Lrp5 produced excess serotonin in the gut and developed low bone mass. Furthermore, turning off Lrp5 in the gut, but not bone, affected serotonin levels and, through serotonin, bone mass.


Yadav, V.K., et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008 Nov 28. 135:825–37.

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