Phosphodiesterase 3 inhibitors boost bone outgrowth

C-type natriuretic peptide (CNP) stimulates skeletal growth by acting on the growth plates of long bones, and a CNP variant is clinically used for achondroplasia treatment. We previously reported that CNP stimulates the autonomic Ca²⁺ influx mediated by TRPM7 channels in growth plate chondrocytes to facilitate extracellular matrix synthesis for bone growth. In this study, we attempted to stimulate CNP signalling using phosphodiesterase (PDE) inhibitors.

Based on gene expression data, we focused on the role of PDE3B in growth plates. We performed imaging, biochemical and histological analyses in growth plate chondrocytes and ex vivo and in vivo analyses on bone and skeletal growth to address the pharmacological effects of PDE3 inhibitors.

The representative PDE3 inhibitors cilostazol and milrinone elevated cGMP levels and activated cell-surface K⁺ channels probably due to protein kinase G-mediated phosphorylation in growth plate chondrocytes. The resulting hyperpolarization likely facilitated TRPM7-mediated Ca²⁺ influx by increasing the Ca²⁺-driving force. Moreover, cilostazol stimulated the elongation of cultured bones and enlarged the body size of juvenile mice.

Several PDE3 inhibitors have been used for clinical treatment of thrombosis, heart failure and asthma, while our observations suggest that the repositioning of PDE3 inhibitors would provide novel medications for skeletal diseases characterized by short stature.