Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum

Area of Science:

• Bone biology
• Endocrinology
• Genetics

Background:

• Loss- and gain-of-function mutations in the Lrp5 gene influence bone formation, leading to osteoporosis or high bone mass.
• Lrp5 is recognized as a Wnt coreceptor, but osteoblast-specific beta-Catenin disruption does not impact bone formation.

Purpose of the Study:

• To investigate the role of Lrp5 in regulating bone formation beyond its known function as a Wnt coreceptor.
• To identify the mechanism by which Lrp5 influences bone mass, particularly in relation to serotonin production.

Main Methods:

• Investigated Lrp5's effect on Tph1 gene expression in the duodenum.
• Utilized genetically modified mice with specific Lrp5 or Tph1 alterations (gut-specific vs. osteoblast-specific).
• Assessed bone formation, bone mass, and serotonin levels in various experimental groups.

Main Results:

• Lrp5 was found to inhibit Tph1 expression, the enzyme responsible for serotonin synthesis in the duodenum.
• Decreased serotonin levels in Lrp5-deficient mice normalized bone formation and bone mass.
• Gut-specific Lrp5 inactivation reduced bone formation independently of beta-Catenin.
• Gut-specific Lrp5 activation or Tph1 inactivation increased bone mass and protected against ovariectomy-induced bone loss.
• Serotonin inhibits osteoblast proliferation via the Htr1b receptor and CREB.

Conclusions:

• Duodenum-derived serotonin acts as a hormone that inhibits bone formation in an Lrp5-dependent manner.
• This study establishes a novel gut-bone signaling pathway involving Lrp5 and serotonin.
• Findings suggest potential therapeutic strategies targeting this axis to enhance bone mass and combat bone diseases like osteoporosis.