A New Lever for Keeping Bones (and Muscles) Resilient

Key takeaways

• Researchers identified a receptor called GPR133 that plays a central role in maintaining bone density, and an experimental compound called AP503 activated it to meaningfully strengthen bones in mice.
• The compound worked by shifting the balance between the cells that build bone and the cells that break it down, and it worked in both healthy mice and mice already showing age-related bone loss.
• The same receptor and compound have separately been shown to strengthen skeletal muscle, hinting at one pathway that could support both systems as people age.
• The bigger picture: understanding how physical forces on bone get translated into biological signals opens a new avenue for preserving structural strength over time.

The switch inside your bones

Bone isn't a static structure. It's constantly being broken down and rebuilt in a continuous renewal cycle, one that depends on keeping bone-forming cells and bone-clearing cells in balance. As that balance shifts with age, bone density can gradually decline, one of the quieter but more consequential changes that comes with getting older.

Researchers at Leipzig University went looking for the biological switches that control this balance, and found a promising one in a receptor called GPR133, part of a family of receptors that sit on cell surfaces and respond to signals from their surroundings, including physical forces.

How one receptor tips the balance

Inside bone tissue, GPR133 responds to mechanical forces and cues from neighboring bone cells. When activated, it shifts the balance between bone-forming cells, called osteoblasts, and bone-clearing cells, called osteoclasts, tipping the scale toward building and maintaining stronger bone.

To test this, researchers used a compound called AP503, identified through a computer-assisted screen as a stimulator of GPR133. In mice, activating the receptor with AP503 meaningfully increased bone strength, and notably, it worked in both mice with normal bone density and mice already showing early, age-related bone loss.

A double benefit: bone and muscle together

One of the more compelling parts of this research is that AP503's reach doesn't stop at bone. In earlier work, the same Leipzig team found that activating this pathway also strengthens skeletal muscle. That combination matters because bone and muscle strength tend to decline together with age, and interventions that support both at once are relatively rare.

Stronger muscles help with mobility and balance, while stronger bone provides the structural resilience to handle everyday physical stress. A single pathway influencing both suggests a more efficient route to supporting the body's overall framework as it ages.

A longevity lens: preserving the body's structural framework

It's easy to think of longevity mainly in terms of metabolism, cognition, or cardiovascular fitness, but the skeleton and musculature are just as central to staying capable and independent for longer. This research adds to a growing understanding that bone remodeling isn't just a passive background process, it's an active system that responds to signals, including mechanical ones, and can potentially be nudged in a favorable direction.

Finding a single receptor that influences both bone and muscle strength also reinforces a broader theme in aging biology: many of the tissues that decline together may share upstream signals worth understanding as a system, rather than one structure at a time.

The takeaway

There's a long road between an experimental compound and something people could actually use. But identifying a specific, targetable switch that strengthens both bone and muscle is a meaningful step, and it points toward a future where preserving structural strength with age might come from working with the body's own signaling pathways rather than around them.

References:

Juliane Lehmann, Hui Lin, Zihao Zhang, Maren Wiermann, Albert M. Ricken, Franziska Brinkmann, Jana Brendler, Christian Ullmann, Luisa Bayer, Sandra Berndt, Anja Penk, Nadine Winkler, Franz Wolfgang Hirsch, Thomas Fuhs, Josef Käs, Peng Xiao, Torsten Schöneberg, Martina Rauner, Jin-Peng Sun, Ines Liebscher. The mechanosensitive adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) enhances bone formation. Signal Transduction and Targeted Therapy, 2025; 10 (1) DOI: 10.1038/s41392-025-02291-y