Osteoporosis is a serious public health problem. Normal bone homeostasis is regulated and maintained by processes known as bone remodeling, which involves bone resorption by osteoclasts and bone formation by osteoblasts. When the balance between the two pathways is disrupted, it leads to osteoporosis. To treat the disease, various drugs in inhibiting bone re-absorption and accelerating bone formation are in use. It is known that dual modulation of the pathways prevents osteoporosis effectively. Although a drug with dual activities (romosozumab) was approved by US FDA in 2019, there is a safety concern of cardiovascular events with this drug. Therefore, new alternatives are needed. Marine microorganisms have been known to be the richest source of bioactive natural products and regarded as an untapped resource for innovative drug discovery. We established diverse libraries of marine microorganisms and utilized phenotypic approaches to identify bioactive compounds of pro-osteogenic and anti-osteoclastogenic dual activities with novel underlying mechanisms. Our approaches led to identification of novel compounds as modulators of bone remodeling pathways. A new class of inhibitors, acredinones in a new benzophenone class, of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation was isolated from the culture broth of the fungus Acremonium sp. (F9A015) previously. Especially acredinone A showed dual activity in both osteoclast and osteoblast differentiation in vitro and good efficacy in an animal disease model of bone formation. Recently austalides (meroterpenoids) were isolated from the marine fungus Penicillium sp (F9A011). The compounds exhibited potent osteoclast differentiation inhibitory activity with ED50 values of 1.9-2.8 μM. Among them, austalide K inhibits osteoclast differentiation and also improves osteoblast differentiation in vitro without cytotoxicity (&gt;20 μM). Finally, we performed a bone erosion assay. Austalide K protected against LPS-induced bone loss in mice, resulting in the improvement of bone mineral density, bone volume, trabecular thickness, and trabecular separation number. However, austalide K did not present satisfactory bioavailability, although it showed profound in vivo activity. Taken together, austalide K may lead to new therapeutic candidates for osteoporosis. In our presentation, our study on its pharmacokinetics and drug metabolism along with bioactivities will be discussed.

Marine fungal products for drug leads to treat osteoporosis

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