Blocking the Axl receptor could offer a new approach to promoting bone formation, according to a study published online on July 6 in Volume 14 of the journal Bone Research. The research was led by Dr. Mubashir Ahmad, who initiated the project with Prof. Dr. Jan Tuckermann at Ulm University and continued as a postdoctoral researcher with Prof. Dr. Anita Ignatius at Ulm University Hospital, Germany.
The researchers found that inhibiting Axl enhances the activity of osteoblasts—cells responsible for building new bone—and increases bone mass in mice. "Our findings identify Axl as a promising therapeutic target for osteoporosis and other bone-related disorders," said Ahmad. "By targeting this receptor, we were able to stimulate bone formation in preclinical models, providing a foundation for developing new anabolic therapies."
To uncover regulators of bone formation, the team performed a kinome-wide RNA interference screen and identified Axl as an unrecognized regulator of osteoblasts. They confirmed these results using genetic approaches and BGB324, a small-molecule inhibitor of Axl, evaluating its effects both in laboratory-grown cells and in mice.
Results showed that blocking Axl promoted maturation of osteoblasts and increased their ability to produce mineralized tissue; mice treated with BGB324 developed greater bone mass due to increased formation activity without significant toxicity observed during the study period.
Further investigation revealed that blocking Axl increased interferon-stimulating gene 15 activity—a protein aiding signals needed for osteoblast maturation—thus removing molecular restraints on these cells' development. "In simple terms, inhibiting Axl removed a molecular signal that normally restrains bone-forming cells, allowing them to mature and build bone more effectively. This newly identified pathway provides fresh insight into how bone formation is regulated," said Tuckermann.
"Our study provides new insight into the molecular mechanisms that regulate osteoblast differentiation and bone formation," said Ignatius. She added that further studies are needed to determine whether targeting Axl can be translated into safe and effective treatments for osteoporosis.
