Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd

Area of Science:

• Bone Biology
• Molecular Endocrinology
• Skeletal Physiology

Background:

• Low-density lipoprotein receptor-related protein 5 (LRP5) is known to regulate bone formation.
• The role of LRP6, a Wnt co-receptor, in postnatal bone metabolism remains incompletely understood.

Purpose of the Study:

• To investigate the function of LRP6 in postnatal bone metabolism using a hypomorphic mouse model.
• To characterize the LRP6 ringelschwanz (rs) mutant protein and its impact on Wnt signaling.

Main Methods:

• Phenotypic analysis of Lrp6(rs/rs) mice using pQCT, bone histomorphometry, and immunohistochemistry.
• Biochemical assessment of bone turnover markers.
• In vitro studies of osteoblast and osteoclast function, including Rankl expression and osteoclastogenesis.

Main Results:

• Lrp6(rs/rs) mice displayed reduced trabecular bone mineral density, lower bone volume, and increased eroded surfaces.
• Increased urinary deoxypyridinoline excretion indicated elevated bone resorption in Lrp6(rs/rs) mice.
• LRP6 rs mutant protein showed impaired plasma membrane targeting due to reduced Mesd interaction, leading to defective Wnt/beta-catenin signaling and increased Rankl expression.

Conclusions:

• LRP6-mediated signaling is essential for maintaining postnatal bone mass, partly by regulating bone resorption.
• The interaction between LRP6 and its chaperone Mesd is critical for LRP6 function in Wnt signaling and bone homeostasis.