Identification of Kukoamine A as an Osteogenic Suppressor and Anti-osteoporosis Drug Target

Abstract Osteoporosis (OP) is a major and growing public health problem characterized by decreased bone mineral density and destroyed bone microarchitecture. Previous studies found that Lycium chinense Mill (LC) has a potent role in inhibiting bone loss. Kukoamine A (KuA), a bioactive compound extract from LC which was responsible for the anti-osteoporosis effect. This study aimed to investigate the anti-osteoporosis effect of KuA isolated from LC in treating OP and its potential molecular mechanism. In this study, network pharmacology and molecular docking were investigated firstly to find the active ingredients of LC such as KuA and the target genes of OP. And then, the anti-osteoporotic effect of KuA in vivo and vitro were investigated and the potential molecular mechanism including inflammation level, cell apoptosis, and oxidative stress were analyzed by dual-energy X-ray absorptiometry (DXA), micro-CT, ELISA, RT-PCR, and Western Blot. A total of 22 active compounds were screened, and we found KuA was identified as the highest active ingredient. PYGM was the target gene associated with a maximum number of active ingredients of LC and regulated KuA. In vivo, KuA treatment significantly increased the bone mineral density and bone structure which promote bone formation and inhibit bone resorption. In vitro, KuA significantly improves osteogenic differentiation and mineralization in cells experiment. In addition, KuA also attenuated inflammation levels, cell apoptosis and oxidative stress level. The results suggest that KuA could protect against the development of OP in osteoblast cells and ovariectomized OP model mice.