A research collaboration between Leipzig University and Shandong University has identified the GPR133 (ADGRD1) adhesion G protein-coupled receptor as a regulator of bone density and strength. The research, published in 2025 in Signal Transduction and Targeted Therapy, presents a compound named AP503 that activates this receptor, demonstrating effects on bone formation in mice.
Background on Osteoporosis
Osteoporosis affects approximately six million people in Germany, with higher prevalence among women and individuals experiencing aging or menopause. The condition is often asymptomatic until a fracture occurs. Current treatments for osteoporosis can slow bone loss but are not designed to reverse it and may involve side effects.
Receptor Identification and Function
The study identified GPR133, a member of the adhesion GPCR subgroup, as a factor in bone formation and maintenance. GPCRs are receptors that transmit signals regulating various bodily processes. The research indicates that GPR133 is involved in the balance between osteoblasts (cells that build bone) and osteoclasts (cells that break down bone).
The receptor is activated by interactions between bone cells and physical forces. Activation generates signals that increase osteoblast activity and decrease osteoclast activity, according to the researchers.
Key Findings from Animal Studies
Mice with genetic alterations affecting the GPR133 gene exhibited low bone density early in life, with characteristics similar to human osteoporosis.
Researchers used computer-assisted screening to identify AP503, a compound that stimulates GPR133. In studies involving both healthy mice and mice with induced osteoporosis, administration of AP503 was associated with increased bone production and bone strength.
Professor Ines Liebscher, lead investigator, stated that AP503 significantly increased bone strength in both groups of mice. The compound appears to mimic the natural activation of the receptor, promoting bone formation and limiting bone breakdown.
Broader Implications and Previous Research
The same research team previously found that activating GPR133 with AP503 improved skeletal muscle strength in mice. Dr. Juliane Lehmann, lead author, noted that the parallel strengthening of bone and muscle may have applications for aging populations, where maintaining both reduces risks of falls, fractures, and loss of independence.
Current Research Status
The researchers are conducting further studies on AP503 and GPR133 to evaluate its utility in other conditions and to understand the receptor's overall function. Further research is necessary before AP503 or similar compounds can be evaluated in humans.
This discovery is the result of over a decade of research at Leipzig University focused on adhesion GPCRs, conducted as part of Collaborative Research Centre 1423.
Related Developments
Two additional studies from 2024 were noted in the same publication:
- A study developed a blood-based, 3D-printable implant that enhanced bone repair in rats by improving the structure of natural blood clots.
- A study identified a hormone called maternal brain hormone (MBH) in female mice that increased bone density and strength.