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Wnt signaling, LRP5 and gut serotonin: Have we been targeting the right pathway for the wrong reasons?
| Content Provider | Semantic Scholar |
|---|---|
| Author | Baron, Roland |
| Copyright Year | 2009 |
| Abstract | The recent discoveries that the human low bone mass Osteoporosis Pseudoglioma Syndrome (OPPG) and the High Bone Mass (HBM) phenotypes were due, respectively, to lossand gain-offunction of the LRP5 receptor (1-3) directed bone research and osteoporosis drug discovery to the Wnt signaling pathway and has resulted in several biologics currently being tested in the clinic for osteo-anabolism. In a stunning and paradigm-shifting manuscript, Dr. Gerard Karsenty and colleagues (4) now report that, contrary to the commonly held belief that the bone mass alterations in OPPG and HBM are due to changes in Wnt signaling in osteoblasts and osteocytes, the skeletal homeostatic function of LRP5 resides in enterochromaffin cells in the duodenum. In these cells the LRP5 receptor negatively regulates the synthesis and secretion of serotonin in the periphery (i.e., independent of serotonin in the brain). In turn, the decrease in circulating serotonin favors osteoblast proliferation and bone formation, with serotonin negatively affecting osteoblasts through the H1b receptor (4). Several studies in the last few years had shown that bone cells, including osteoclasts, express receptors for serotonin (5-8) and that the effects of serotonin reuptake inhibition lead to a marked decrease in bone formation and bone density in mice and also to increased fracture risk in humans (9-10), although there may be opposite effects on cortical bone, which was not studied here. The truly new findings in the current study from Yadav et al. are 1) the identification of the osteoblast serotonin receptor; 2) the strengthened evidence for a negative influence of serotonin on bone formation and more importantly; 3) the finding that LRP5 plays a critical role in the regulation of serotonin synthesis in the gut (Fig. 1). |
| Starting Page | 86 |
| Ending Page | 93 |
| Page Count | 8 |
| File Format | PDF HTM / HTML |
| DOI | 10.1138/20090365 |
| Volume Number | 6 |
| Alternate Webpage(s) | http://triggered.stanford.clockss.org/ServeContent?url=https://knowledgeenvironment.stanford.clockss.org/2009/bonekey_2009_bonekey20090365_xml_pdf/bonekey20090365.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
