Researchers have identified a promising new therapeutic application for phosphodiesterase 3 (PDE3) inhibitors, drugs currently approved for treating heart failure, thrombosis, and asthma. A study published in the British Journal of Pharmacology on June 2, 2025, demonstrates that these medications can stimulate bone growth by enhancing key cellular signaling pathways in cartilage cells.
The research team, led by Associate Professor Atsuhiko Ichimura from Ritsumeikan University and Professor Hiroshi Takeshima from Kyoto University, investigated how PDE3 inhibitors affect bone development through both laboratory culture studies and live animal experiments.
Mechanism of Action in Bone Growth
Bone elongation occurs through the activity of specialized cartilage cells called chondrocytes, located at the growing ends of bones in structures known as growth plates. These cells synthesize extracellular matrix (ECM), which serves as the foundation for new bone formation.
The process begins when C-type natriuretic peptide (CNP), a peptide hormone, binds to receptors on chondrocytes and triggers a complex signaling cascade. This binding activates cyclic guanosine monophosphate (cGMP), which in turn activates protein kinase G (PKG). PKG then phosphorylates membrane ion channels, causing the cell to hyperpolarize through potassium ion efflux.
This hyperpolarization opens calcium channels, particularly TRPM7 channels, allowing calcium ions to flow into the chondrocytes. The resulting calcium influx activates downstream signaling molecules that drive ECM production and promote bone growth.
PDE3 normally acts as a brake on this process by converting cGMP to GMP, effectively dampening the CNP signaling cascade. The researchers hypothesized that inhibiting PDE3 would maintain higher cGMP levels and amplify the bone growth signals.
Experimental Results
When the team applied cilostazol, a representative PDE3 inhibitor, to cultured metatarsal bones, they observed significant increases in bone outgrowth compared to control cultures. "In cilostazol-treated bones, round and columnar chondrocyte zones were preferentially expanded," reported graduate student Takaaki Kawabe.
The in vivo experiments proved equally promising. Three-week-old mice treated with intraperitoneal injections of cilostazol for four weeks showed significant increases in body length (naso-anal length) compared to control animals, with no adverse effects on body weight.
Biochemical analysis revealed that cGMP content in cilostazol-treated cultured bones was approximately 1.7 times higher than in control cultures, confirming that PDE3 inhibitors successfully prevent cGMP degradation and enhance the CNP signaling pathway.
Clinical Implications
"Our research suggests that PDE3 inhibitors could be repurposed for treating conditions characterized by short stature, such as achondroplasia or idiopathic short stature," stated Dr. Ichimura and Professor Takeshima.
The potential for drug repurposing is particularly attractive because PDE3 inhibitors already have established safety profiles from their use in cardiovascular conditions. This could accelerate the development of treatments for growth disorders without requiring entirely new drug discovery programs.
However, the researchers emphasize important safety considerations. The study notes that "self-administration of commercially available PDE3 inhibitors is strictly prohibited, as it is unlikely to promote bone growth and could cause serious side effects, such as hypotension and impaired blood clotting."
Future Directions
The findings lay groundwork for potential clinical trials exploring PDE3 inhibitors in pediatric populations affected by skeletal growth disorders. Combined with existing therapeutic approaches, these inhibitors could offer new hope for patients with limited treatment options.
Dr. Ichimura explained the research motivation: "We previously reported that CNP stimulates autonomic Ca2+ influx mediated by TRPM7 channels in growth plate chondrocytes to facilitate ECM synthesis for bone growth. In this study, we attempted to stimulate CNP signaling using PDE inhibitors."
The research represents a significant advance in understanding the molecular mechanisms governing bone development and demonstrates how existing drugs might be repurposed to address unmet medical needs in skeletal disorders.
