High Bone Mass-Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo

Area of Science:

• Genetics and Molecular Biology
• Bone Biology and Metabolism
• Pharmacology

Background:

• Certain missense mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are linked to high bone mass (HBM) phenotypes in humans.
• In vitro studies suggest that HBM-associated LRP5 variants resist inhibition by secreted antagonists like sclerostin (SOST) and Dickkopf homolog-1 (DKK1).

Purpose of the Study:

• To investigate the in vivo effects of SOST and DKK1 on Lrp5 high bone mass (HBM) knock-in mouse models.
• To determine if HBM LRP5 receptors exhibit differential resistance to SOST and DKK1 inhibition.

Main Methods:

• Generation of Lrp5 knock-in mouse models harboring human p.A214V or p.G171V missense mutations.
• Cross-breeding of Lrp5 HBM mice with transgenic mice overexpressing SOST or DKK1.
• Assessment of bone mineral density (BMD), bone mineral content (BMC), and bone structure parameters.

Main Results:

• SOST overexpression significantly reduced bone parameters in wild-type mice but not in Lrp5 p.G171V and p.A214V mice.
• DKK1 overexpression reduced bone parameters in wild-type and p.A214V mice, with a lesser effect on p.G171V mice.
• These findings support the hypothesis that HBM LRP5 mutations confer resistance to SOST and DKK1.

Conclusions:

• In vivo data confirm that LRP5 variants associated with high bone mass provide resistance to SOST and DKK1.
• HBM LRP5 receptors demonstrate differential sensitivity to inhibition by SOST and DKK1.
• These findings elucidate the in vivo mechanism of LRP5-mediated high bone mass.