Ailanthone hijacks ERK/NF-κB cascade to attenuate osteoclastogenesis for osteoporosis.

Abstract

BACKGROUND: Osteoporosis is a serious bone disease, it can eventually lead to disability. However, no safe or effective intervention is currently available. Therefore, there is an urgent need to develop effective drugs that reduce bone loss and treat osteoporosis. PURPOSE: This study aimed to ascertain the potential of ailanthone (AIL), a natural small molecule, as a therapeutic drug for alleviating the progression of osteoporosis. METHODS: By screening of a library of natural compounds; in vitro assays for examining the inhibition of osteoclast differentiation by AIL: in vivo assays for detecting the anti-osteoclastogenesis activity of AIL using mimicking progressive bone loss mice model and the other simulating postmenopausal osteoporosis mice model. Identification and characterisation of the binding of AIL to extracellular signal-regulated kinase 2 (ERK2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, microscale thermophoresis; various assays for examining the dependence of AIL's anti-osteoclastogenesis activity on ERK2. RESULTS: This study discovered AIL, a potent inhibitor of osteoclastogenesis from a screened library of natural compounds. In vitro studies demonstrated that AIL attenuated RANKL-induced osteoclast differentiation. Additionally, AIL administration decreased osteoclast populations and their bone-degrading activities. AIL was discovered to target ERK2, specifically the Methionine-108 (Met-108) site, which is presumed to contribute to its anti-osteoclastogenic properties. Further analysis indicated that AIL blocks ERK1/2 phosphorylation, thereby influencing the NF-κB signaling cascade. CONCLUSIONS: Collectively, these findings demonstrate AIL, that can significantly inhibit osteoclastogenesis linked to inflammaging, opening up novel avenues for osteoporosis treatment strategies and other ERK related diseases.