Targeting autophagy by natural product Ursolic acid for prevention and treatment of osteoporosis.

With the growth of the aging population, osteoporosis is becoming a global health problem. Ursolic acid (UA) is an active ingredient existed in a variety of foods and nature plants and owns plenty of pharmacological effects especially in treating metabolic disease. Our predication from network pharmacology hinted that UA has potential for ameliorating osteoporosis. Firstly through in vivo experiment, we confirmed that UA administration obviously protected against ovariectomy (OVX)-induced osteoporosis in rats by improving microarchitectural deterioration of trabecular bone (P < 0.001), decreasing numbers of TRAP positive osteoclast in vertebra (P < 0.001), as well as decreasing serum osteoclast-specific cytokines release (P < 0.001). Besides, UA ameliorated kidney damage secondary to OVX-induced osteoporosis by ameliorating glomerular atrophy, decreasing BUN and creatinine levels in OVX rats. In vitro, UA noticeably decreased osteoclastic-special marker proteins c-Fos and NFATc1 expressions (P < 0.001) in response to RANKL stimulation in macrophagy. Importantly, autophagy pathway was activated in the process of osteoclast differentiation and blocked by UA pretreatment. Furthermore, autophagy inhibitors suppressed osteoclast differentiation (P < 0.001). Collectively, UA may ameliorate osteoporosis by suppressing osteoclast differentiation mediated by autophagy. Our research provides scientific support for UA treating osteoporosis and offers an optimal dose for daily intake of UA safely to prevent bone diseases.