Activating GPR133 Restores Bone Strength in Mice — A Potential Path to Reverse Osteoporosis

A new preclinical study identifies the cell-surface receptor GPR133 (also known as ADGRD1) as a pivotal regulator of bone formation and strength. Researchers from the University of Leipzig (Germany) and Shandong University (China) report that stimulating GPR133 increases osteoblast activity and strengthens bone in mice, while loss of the receptor produces osteoporosis-like weakness.

Key findings from the mouse study

The team used two complementary approaches: genetic deletion of GPR133 and pharmacologic activation with a small molecule called AP503. Mice lacking the GPR133 gene developed weaker bones with features resembling osteoporosis. By contrast, when GPR133 was present and stimulated by AP503, markers of bone formation rose and bone strength improved measurably.

According to Ines Liebscher, a biochemist involved in the work, "Using AP503, which was recently identified by a computer-assisted screen as a stimulator of GPR133, we were able to significantly increase bone strength in both healthy and osteoporotic mice." In the experiments AP503 acted like a biological switch that ramped up osteoblast activity.

Synergy with exercise and translational potential

The researchers also found that combining AP503 treatment with exercise produced greater gains in bone strength than either intervention alone, suggesting GPR133 activation can work in concert with mechanical stimulation to build stronger bone.

While these results are limited to animal models, the underlying biology is likely conserved in humans. The authors suggest that therapies targeting GPR133 could someday both fortify healthy bone and rebuild bone lost to disease, for example during menopause. The study appears in the journal Signal Transduction and Targeted Therapy.

Context: other promising preclinical advances

The GPR133 findings join a growing body of laboratory research that aims to harness the body's natural repair systems to treat skeletal disease. In 2024, researchers described a "biocooperative regenerative" blood-derived implant that uses synthetic peptides to enhance the clot-derived scaffold during healing; in rat tests the 3D-printable gel improved bone repair. Separately, a team at the University of California, San Francisco identified a hormone dubbed maternal brain hormone (MBH) that produced unusually dense, strong bones in mouse experiments.

Caveats and next steps

These discoveries are promising but preliminary. Success in mice does not guarantee safety or effectiveness in humans. Challenges ahead include verifying that GPR133 activation is safe long-term, optimizing AP503 or related compounds for humans, and testing efficacy in diverse models of bone loss. If subsequent studies are positive, therapies that target GPR133 could broaden the arsenal against osteoporosis beyond existing treatments that mainly slow bone loss.

"The newly demonstrated parallel strengthening of bone once again highlights the great potential this receptor holds for medical applications in an aging population," said molecular biologist Juliane Lehmann of the University of Leipzig.

Source: Study published in Signal Transduction and Targeted Therapy. Quotes are from the study authors.