Penicopeptide A (PPA) from the deep-sea-derived fungus promotes osteoblast-mediated bone formation and alleviates ovariectomy-induced bone loss by activating the AKT/GSK-3β/β-catenin signaling pathway.

The potential of marine natural products as effective drugs for osteoporosis treatment is an understudied area. In this study, we investigated the ability of lead compounds from deep-sea-derived Penicillium solitum MCCC 3A00215 to promote bone formation in vitro and in vivo. We found that penicopeptide A (PPA) promoted osteoblast mineralization among bone marrow mesenchymal stem cells (BMSCs) in a concentration-dependent manner, and thus, we selected this natural peptide for further testing. Our further experiments showed that PPA significantly promoted the osteogenic differentiation of BMSCs while inhibiting their adipogenic differentiation and not affecting their chondrogenic differentiation. Mechanistic studies showed that PPA binds directly to the AKT and GSK-3β and activates phosphorylation of AKT and GSK-3β, resulting in the accumulation of β-catenin. We also evaluated the therapeutic potential of PPA in a female mouse model of ovariectomy-induced systemic bone loss. In this model, PPA treatment prevented decreases in bone volume and trabecular thickness. In conclusion, our in vitro and in vivo results demonstrated that PPA could promote osteoblast-related bone formation via the AKT, GSK-3β, and β-catenin signaling pathways, indicating the clinical potential of PPA as a candidate compound for osteoporosis prevention.