Aptamer Apc001 blocks sclerostin loop3-LRP4 interaction, preventing bone loss without increasing arterial stiffness

Mechanical unloading, such as during prolonged bed rest or spaceflight, causes significant bone loss and cardiovascular deconditioning. Elevated sclerostin expression is a key contributor to this bone loss. While genetic Sost knockout or antibody-mediated sclerostin inhibition (targeting loop2, e.g., romosozumab) can counteract bone loss, commercially available sclerostin antibodies have been linked to severe cardiovascular events in postmenopausal osteoporotic patients. A critical gap exists for developing a precise sclerostin inhibition strategy that preserves bone density without increasing cardiovascular risk.

Researchers investigated the role of sclerostin loop3 under mechanical unloading conditions in mice. They used Sost loop3-/- mice with a specific deficiency in sclerostin loop3, and treated mice with the tailor-made aptamer Apc001 to specifically inhibit sclerostin loop3. For comparison, Sost knockout mice and romosozumab treatment were also evaluated. The study assessed unloading-induced bone loss and arterial stiffness. Mechanistically, they identified that sclerostin loop3 binds to LRP4 in osteoblasts. Further experiments involved osteoblast-specific Lrp4 knockout (OB.Lrp4-/- mice) and blocking the sclerostin loop3-LRP4 interaction via Lrp4m mutation or a LRP4 peptide tool.

Specific inhibition of sclerostin loop3 proved effective and safe. Either sclerostin loop3-specific deficiency in Sost loop3-/- mice or pharmacologic inhibition by aptamer Apc001 counteracted unloading-induced bone loss without increasing arterial stiffness. In stark contrast, Sost knockout or romosozumab treatment significantly increased unloading-induced arterial stiffness in mice. These findings highlight sclerostin loop3 as a therapeutic target with cardiovascular safety. Mechanistically, the study identified that sclerostin loop3 directly bound to LRP4 in osteoblasts under mechanical unloading. > Osteoblast-specific Lrp4 knockout (OB.Lrp4-/- mice) counteracted unloading-induced bone formation reduction and bone loss. Blocking the sclerostin loop3-LRP4 interaction via Lrp4m mutation or a LRP4 peptide tool also promoted bone formation, confirming the critical role of this interaction in sclerostin's inhibitory effect.