The mechanism underlying the TC-G 1008 rescue of reactive oxygen species (ROS)-induced osteoblast apoptosis by the upregulation of peroxiredoxin 1.

Abstract

Osteoporosis is a common bone disease in the elderly with high morbidity and mortality. Previous studies have shown ROS-revulsive osteoblast apoptosis to be involved in the pathogenesis of osteoporosis. At present, a research hotspot exists on the topic of the ROS-targeted clinical treatment of osteoporosis. TC-G 1008, a potent and selective GPR39 agonist, exerts a conspicuous influence on a myriad of cellular processes, ranging from cellular redox status, to gene expression, to cell apoptosis. However, the underlying mechanism by which TC-G 1008 regulates osteoblast function under oxidative stress has not yet been elucidated. The purpose of this study was to investigate the effect and underlying mechanism of TC-G 1008 in the rescue of ROS-induced apoptosis by upregulating peroxiredoxin (Prx1). In this study, experimental results demonstrated that TC-G 1008 could activate GPR39, which then accelerated ROS obliteration and apoptosis inhibition in osteoblasts via Prx1 upregulation through the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Interestingly, being regarded as an 'information' molecule rather than an anti-oxidase molecule, Prx1 was shown to restrict the dissociation of the apoptosis signal-regulating kinase 1 (ASK1)/thioredoxin (Trx) under oxidative stress, which signified the activation of the ASK1 pathway, thereby resulting in the suppression of apoptosis. In summary, this study explores the double mechanism of TC-G 1008 in osteoblast apoptosis amelioration under oxidative stress through (i) ROS elimination and (ii) ASK1/Trx signal suppression, both of which contribute to increased Prx1 expression, and the results suggest that TC-G 1008 has great potential in the clinical treatment of osteoporosis.