A novel BMP2 secretagogue ameliorates glucocorticoid induced oxidative stress in osteoblasts by activating NRF2 dependent survival while promoting Wnt/β-catenin mediated osteogenesis

In our previous study, a novel BMP2 secretagogue was synthesized belonging to a class of galloyl conjugates of flavanones, with remarkable osteogenic potential that promoted bone regeneration. We aimed to establish the protective effect of our compound against bone loss that co-exists with excess Glucocorticoid (GC) therapy. GC therapy induces osteoblast damage leading to apoptosis by increasing reactive oxygen species (ROS). Our results delineate that compound 5e (a BMP2 secretagogue) activates NRF2 signalling to counter the disturbed cellular redox homeostasis and escalate osteoblast survival as assessed by Western blot and immunocytochemistry. Depletion of NRF2 by siRNA blocked activation of the NRF2/HO-1 pathway, magnified oxidative stress, increased apoptosis and abrogated the protective effects of compound 5e. 5e, on the other hand, increased ALP, mineralization activity, and promoted osteoblast differentiation by activating WNT/β-catenin signalling in BMP2 dependent manner, validated by Western blot of WNT3A, SOST, GSK3-β and β-catenin nuclear translocation. Treatment of 5e in presence of BMP inhibitor noggin attenuated the osteogenic efficacy and minimized Wnt//β-catenin signalling in presence of dexamethasone. Our compound prevents GC challenged trabecular and cortical bone loss assessed by micro-CT and promotes bone formation and osteocyte survival determined by calcein labelling and TUNEL assay in GC treated animals. The osteogenic potential of the compound was authenticated by bone turnover markers. On a concluding note, compounds with BMP upregulation can be potential therapeutics for the prevention and treatment of glucocorticoid-induced osteoporosis.