Versicotide G suppresses osteoclastogenesis and prevents osteolysis

Excessive formation and function of osteoclasts cause various osteolytic bone diseases. Natural products are a potential source for the discovery of new therapeutic candidates to treat bone destruction diseases. In this study, chemical informatics and bioassay guided examination of the marine-derived Aspergillus versicolor F77 fungus chemically resulted in the isolation of seven cyclopeptides, of which versicotides G-J ( 1 – 4 ) are new cyclohexapeptides. Their structures were identified by spectroscopic data in association with Marfey method and single crystal X-ray diffraction data for configurational assignments. Bioassay revealed that versicotide G ( 1, VG) is the most active among the analogs to suppress the receptor activator of nuclear factor-KB ligand (RANKL)-induced osteoclastogenesis in bone marrow derived monocytes (BMMs) without affecting BMMs viability. VG also suppressed RANKL-induced actin-ring formation and resorbing function of osteoclast dose-dependently. Mechanistically, VG attenuated RANKL-induced intracellular calcium elevation by inhibiting PLCγ1 phosphorylation and blocking the activation of downstream phosphatase calcineurin. In addition, VG abrogated the expression and translocation of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), leading to the downregulation of the expression of osteoclast-specific genes and the abolishment of the osteoclast formation. In the in vivo test, VG suppressed osteoclast formation and bone loss in Ti-induced calvarial osteolytic mouse model.These findings imply that VG is a promising candidate for the remedy of bone destruction-related diseases.