Because existing therapies can have limitations and side effects, researchers are looking for new biological targets that could lead to more effective ways of preserving or rebuilding bone. Scientists at Leipzig University have now identified one such target in GPR133, a receptor that appears to play an important role in keeping bones strong.

A Little-Known Receptor With a Major Role in Bone Health

GPR133 belongs to a group known as adhesion G protein-coupled receptors. These receptors sit on the surface of cells and help them respond to signals from their surroundings. Although this family of receptors is still not fully understood, the new findings suggest GPR133 is closely involved in the processes that build and maintain healthy bone.

“If this receptor is impaired by genetic changes, mice show signs of loss of bone density at an early age – similar to osteoporosis in humans. Using the substance AP503, which was only recently identified via 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, lead 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 stimulating 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

Inside bone tissue, GPR133 responds to physical forces and interactions between nearby bone cells. When the receptor is activated, it sets off signaling that changes the balance between the cells that build bone and those that break it down.

Bone-forming cells (osteoblasts) are responsible for producing new bone tissue. Bone-resorbing cells (osteoclasts), by contrast, remove old bone as part of the skeleton’s normal cycle of renewal. Healthy bones depend on maintaining the right balance between these two processes.

Activation of GPR133 encourages the activity of osteoblasts while reducing the activity of osteoclasts. This shifts the balance toward stronger and more durable bone.

AP503 appears to imitate 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 potential application would be osteoporosis associated with menopause, when declining hormone levels can accelerate bone loss in women.

Potential Benefits for Both Bone and Muscle

The findings could have broader implications because AP503 may affect more than the skeleton.

In an earlier study, researchers at Leipzig University had already found that activation with AP503 also strengthens skeletal muscle.

“The newly demonstrated parallel strengthening of bone once again highlights the great potential this receptor holds for medical applications in an aging population,” says Dr. Juliane Lehmann, lead author of the study and a researcher at the Rudolf Schönheimer Institute of Biochemistry.

A treatment capable of improving both 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 support mobility and stability, while stronger bones can reduce vulnerability to fractures.

The Leipzig team is now pursuing several follow-up projects aimed at understanding GPR133 more fully. Researchers are also investigating whether AP503 could have applications in other diseases and are continuing to examine the receptor’s wider functions throughout the body.

Leipzig’s Longstanding Research Into GPR Receptors

For more than a decade, Leipzig University has made adhesion G protein-coupled receptors a major research priority through Collaborative Research Center 1423, Structural Dynamics of GPCR Activation and Signaling.

The program focuses on understanding how these receptors change shape, become activated, and transmit signals inside cells. Leipzig University is internationally recognized as a leading center for research in this area.

The study was led by Professor Chloe Bloom, Clinical Associate Professor in Respiratory Epidemiology at the National Heart & Lung Institute, Imperial College London, UK, and presented by Dr. Bohee Lee.

Exploring GLP 1 Drugs and Lung Health

Dr. Bloom said: “GLP-1 receptor agonists are widely used to treat type 2 diabetes and obesity. Previous research suggests that they may have anti-inflammatory effects and may improve lung-related outcomes. However, asthma and COPD outcomes have not been included as outcomes in GLP-1 drug trials.

“We wanted to use real-world health records to investigate whether people with asthma or COPD who started GLP-1 receptor agonists had fewer acute respiratory attacks.”

To investigate that question, the researchers analyzed electronic medical records from the UK. They carried out four parallel studies, each involving between 20,000 and 22,000 people who had started treatment with either a GLP-1 medication or a different type of diabetes drug known as a sulfonylurea.

The results suggested that people with airway diseases such as asthma and COPD who received GLP-1 therapies experienced fewer asthma attacks and COPD flare-ups than comparable patients who were prescribed other diabetes medications.

Semaglutide Showed the Strongest Effect

Among the GLP-1 drugs examined, semaglutide appeared to stand out, particularly for people with asthma.

Bloom explains: “The effect was strongest with semaglutide, especially in people with asthma, where use of semaglutide appears to be associated with nearly a 40% reduction in asthma attacks. Semaglutide also led to a 20% reduction in COPD flare-ups.”

The findings suggest that people who already qualify for GLP-1 receptor agonists because they have obesity or type 2 diabetes could potentially receive an additional benefit for their respiratory health.

However, Bloom emphasized that the results are not enough to recommend these medications specifically as treatments for asthma or COPD.

She explains: “The findings from this study are encouraging, but they should not change treatment decisions on their own. People with asthma or COPD should not start GLP-1 receptor agonists specifically for their lung condition outside current prescribing guidance. While the findings suggest that some people taking GLP-1 receptor agonists may experience fewer respiratory attacks, this needs confirmation in clinical trials.”

Why Metabolic Health May Matter for the Lungs

Dr. Alexander Mathioudakis, Chair of the European Respiratory Society’s Group on Airway Pharmacology and Treatment and Senior Lecturer in Respiratory Medicine at the University of Manchester, UK, was not involved in the research.

He said: “Obesity and metabolic dysfunction are common in airways disease and are often under-recognized as problems that can and should be addressed.

“This is one of the largest real-world studies to investigate GLP-1 receptor agonists and airways disease, and one of the first to examine whether effects differ between individual GLP-1 receptor agonists.

“It highlights the need to consider metabolic health as part of respiratory care. It also supports the case for including respiratory outcomes, such as asthma attacks and COPD exacerbations, in future trials of metabolic therapies.

“We need clinical trials that include respiratory outcomes, such as asthma attacks, COPD exacerbations, lung function, symptoms and quality of life, to determine whether metabolic treatments could become part of a broader, more personalized approach to managing airways disease.”