Antiresorptive Effects of Cochinchinone A in a Rankl‐Induced Osteoporotic Medaka Model

ABSTRACT

This study investigates the osteoprotective potential of cochinchinone A ( CoA ), a phenolic xanthone isolated from Cratoxylum cochinchinense , using a RANKL‐induced transgenic medaka (rankl:HSE:CFP, line d1) model of osteoporosis. CoA was extracted and structurally confirmed by NMR and ESI‐HRMS analysis. Heat‐shock induction at 39°C triggered Rankl overexpression and subsequent bone resorption in Rankl larvae. Larvae were treated with various concentrations of CoA and bone mineralization were evaluated. In Rankl‐stimulated larvae, CoA markedly preserved bone mineralization compared with untreated osteoporotic controls. Treatment with 4.5 µM CoA enhanced skeletal mineralization and attenuated bone resorption, achieving a bone protection index of up to 17%, comparable to that achieved with the positive control, alendronate (50 µg.mL ⁻¹ ). Importantly, CoA exhibited no detectable developmental toxicity in wild‐type larvae at concentrations up to 223 µM. Molecular docking analysis revealed that CoA binds favorably to a critical Rankl interface pocket involved in RANK recognition (binding affinity: −6.9 kcal/mol), forming hydrogen bonds and hydrophobic interactions that suggest an OPG‐mimicking mechanism underlying its antiresorptive effects observed in vivo. These findings demonstrate that CoA exerts antiresorptive and bone‐protective effects in vivo, highlighting its potential as a natural lead compound for osteoporosis therapy.