81 / 2021-10-10 22:17:13

Briarane-type praelolide suppresses osteoclastogenisis in vitro and in vivo by inhibition of protein kinase c-src

osteoclast, c-src , briarane

Abstract:

Bone homeostasis is a balance between bone-resorbing osteoclasts and bone-forming osteoblasts, while tipping the balance in favor of osteoclasts resulted in bone destructive diseases. Natural products are a promising source to attenuate the osteoclast formation and relevant diseases of bone loss. Herein, a total of 45 briarane-type analogues from gorgonian Junceella juncea were isolated, and their structures were determined by extensive analyses of spectroscopic data. All of them showed significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages in vitro. The investigation of structure-activity relationship data indicated that praelolide was the most active to inhibit osteoclast development due to the decreased number of multinucleated tartrate-resistance acid phosphatase positive cells, suppression of the actin ring formation, blockage of bone resorption, and downregulation of osteoclast-specific marker genes. Mechanistically, praelolide abolished RANKL-induced NFATc1 nuclear translocation by suppressing c-src kinase, which control calcium oscillation by mediating phosphorylation of PLCγ2. Reverse docking showed an excellent affinity between praelolide and c-src, implying c-src as a possible target of praelolide. Furthermore, praelolide suppressed RANKL-induced activation of MAPK and NFκB signal pathways. Moreover, praelolide promoted osteogenesis in glucocorticoid-treated zebrafish in vivo. Hence, praelolide may be a potential candidate for prevention osteoclast-mediated bone destructive diseases.