RSPO3 is important for trabecular bone and fracture risk in mice and humans

Area of Science:

• Bone Biology and Genetics
• Osteoporosis Research
• Molecular Mechanisms of Skeletal Health

Background:

• Osteoporotic fractures are a growing global health concern with increasing age.
• Genetic studies have linked the RSPO3 locus to fracture risk, but the specific gene and mechanism remain unclear.

Purpose of the Study:

• To identify the causal gene at the RSPO3 locus associated with fracture risk.
• To elucidate the mechanism by which RSPO3 influences bone health and fracture susceptibility.

Main Methods:

• Analysis of genetic association signals at the RSPO3 locus in human populations.
• Measurement of RSPO3 expression (mRNA and protein) and its correlation with bone mineral density and fracture risk.
• Investigation of RSPO3 expression in bone cells (osteoprogenitors, osteoblasts) and its role in mouse models.
• Mechanistic studies on RSPO3's effect on osteoblast proliferation and differentiation.

Main Results:

• The fracture-reducing allele at RSPO3 is associated with increased RSPO3 expression, higher trabecular bone mineral density, and reduced distal forearm fracture risk in humans.
• RSPO3 is expressed in osteoblasts, with osteoblast-derived RSPO3 being a primary source in bone.
• RSPO3 regulates vertebral trabecular bone mass and strength in adult mice.
• RSPO3 promotes osteoblast proliferation and differentiation in a cell-autonomous manner.

Conclusions:

• RSPO3 is identified as the causal gene regulating bone mass and strength.
• RSPO3 plays a significant role in controlling vertebral trabecular bone mass and bone strength in mice.
• RSPO3 influences fracture risk in humans, highlighting its therapeutic potential for osteoporosis.