Osteoporosis, a condition that weakens bones and increases the risk of fractures, affects millions of people and remains a major challenge for doctors seeking safe treatments that can be used for long periods. About six million people, most of them women, are affected in Germany alone.
Because existing therapies can have limitations and side effects, researchers are looking for new biological targets that could lead to more effective ways to preserve or rebuild bone. Scientists at the University of Leipzig have identified one such target in GPR133, a receptor that appears to play an important role in maintaining strong bones.
A little-known receptor with an important role in bone health
GPR133 belongs to a group known as adhesion G protein-coupled receptors. These receptors are found on the surface of cells and help them respond to signals from their environment. Although this family of receptors is not yet fully understood, the new findings suggest that GPR133 is closely involved in the processes that build and maintain healthy bones.
“If this receptor is affected by genetic changes, the mice show signs of loss of bone density at an early age, similar to osteoporosis in humans. Using the substance AP503, which was recently identified through a computer-assisted screen as a stimulator of GPR133, we were able to significantly increase bone strength in both healthy and osteoporotic mice,” explains Professor Ines Liebscher, principal investigator of the study from the Rudolf Schönheimer Institute of Biochemistry at the Faculty of Medicine.
The results point to GPR133 as a potentially valuable target for future osteoporosis treatments. The researchers found that stimulation of the receptor with AP503 increased bone strength not only in healthy mice, but also in mice with osteoporosis-like bone loss.
How GPR133 Helps Build Stronger Bones
Within bone tissue, GPR133 responds to physical forces and interactions between nearby bone cells. When the receptor is activated, it activates signaling that changes the balance between the cells that form bone and those that break it down.
Bone-forming cells (osteoblasts) are responsible for producing new bone tissue. In contrast, bone resorption cells (osteoclasts) remove old bone as part of the normal skeletal renewal cycle. Healthy bones depend on maintaining the proper balance between these two processes.
Activation of GPR133 stimulates osteoblast activity while reducing osteoclast activity. This shifts the balance toward stronger, more durable bone.
AP503 appears to mimic the natural process that activates GPR133. That raises the possibility that the compound could eventually be used to increase bone strength or help restore bone that has already been weakened. One possible application would be osteoporosis associated with menopause, when declining hormone levels can accelerate bone loss in women.
Potential benefits for both bones and muscles
The findings could have broader implications because AP503 may affect more than the skeleton.
in a previous studyResearchers at the University of Leipzig had already discovered that activation with AP503 also strengthens skeletal muscle.
“The recently demonstrated parallel strengthening of bone highlights once again the great potential this receptor has for medical applications in an aging population,” says Dr. Juliane Lehmann, lead author of the study and researcher at the Rudolf Schönheimer Institute of Biochemistry.
A treatment capable of improving bone and muscle strength could be especially relevant for older adults, who often experience declines in both tissues at the same time. Maintaining stronger muscles can also promote mobility and stability, while stronger bones can reduce vulnerability to fractures.
The Leipzig team is carrying out several monitoring projects aimed at better understanding GPR133. The researchers are also investigating whether AP503 might have applications in other diseases and continue to examine the receptor’s broader functions throughout the body.
Leipzig’s long investigation into GPR receivers
For more than a decade, the University of Leipzig has made adhesion G protein-coupled receptors an important research priority through Collaborative Research Center 1423, Structural dynamics of GPCR activation and signaling.
The program focuses on understanding how these receptors change shape, activate, and transmit signals within cells. The University of Leipzig is internationally recognized as a leading research center in this field.