Briarane-type diterpenoids suppress osteoclastogenisis by regulation of Nrf2 and MAPK/NF-kB signaling pathway

Area of Science:

• Marine Natural Products Chemistry
• Skeletal Biology
• Pharmacology

Background:

• Excessive osteoclast activity disrupts bone remodeling, leading to skeletal diseases like osteoporosis.
• Natural products offer potential therapeutic agents for bone loss conditions.

Purpose of the Study:

• To isolate and identify compounds from gorgonian corals with anti-osteoclastogenic activity.
• To investigate the structure-activity relationship (SAR) of briarane-type diterpenoids.
• To elucidate the mechanism of action of the most potent compound, junceellolide D (JD).

Main Methods:

• Bioassay-guided isolation of compounds from Dichotella gemmacea.
• Structure elucidation of 39 briarane-type analogues using spectroscopic data.
• In vitro assays to assess inhibition of osteoclast differentiation, actin ring formation, and bone resorption.
• Analysis of gene expression and signaling pathway activation (Nrf2, NF-κB, MAPK).

Main Results:

• Junceellolide D (JD) significantly inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs).
• JD suppressed osteoclast formation, actin ring development, and bone resorption, with 28 new analogues also synthesized.
• Mechanistically, JD enhanced nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) stability and nuclear translocation, boosting antioxidant enzymes and reducing reactive oxygen species (ROS).
• JD also inhibited RANKL-stimulated NF-κB and MAPK signaling pathways.

Conclusions:

• Junceellolide D is a potent inhibitor of osteoclastogenesis, acting through Nrf2 activation and suppression of NF-κB and MAPK pathways.
• JD represents a promising lead compound for developing novel therapeutics against osteoclast-mediated bone diseases.
• Further research into JD and its analogues could yield new treatments for osteoporosis and related bone disorders.