Identifying Marine-Derived Tanzawaic Acid Derivatives as Novel Inhibitors against Osteoclastogenesis and Osteoporosis via Downregulation of NF-κB and NFATc1 Activation

To discover novel osteoclast-targeting antiosteoporosis
leads from
natural products, we identified 40 tanzawaic acid derivatives, including
22 new ones (1–8, 14–19, 27–32, 37, and 38), from the South China Sea mangrove-derived
fungus Penicillium steckii SCSIO 41025.
Penicisteck acid F (2), one of the new derivatives showing
the most potent NF-κB inhibitory activity, remarkably inhibited
osteoclast generation in vitro. Mechanistically, 2 reduced RANKL-induced IκBα degradation, NF-κB
p65 nuclear translocation, the activation and nuclear translocation
of NFATc1, and the relevant mRNA expression. NF-κB p65 could
be a potential molecular target for 2, which has been
further determined by the cellular thermal shift assay, surface plasmon
resonance, and the gene knock-down assay. Moreover, 2 could also alleviate osteoporosis in ovariectomized mice by reducing
the quantities of osteoclasts. Our finding offered a novel potential
inhibitor of osteoclastogenesis and osteoporosis for further development
of potent antiosteoporosis agents.