// Feng Wang 1,* , Peipei Yin 1,* , Ye Lu 1 , Zubin Zhou 1 , Chaolai Jiang 1 , Yingjie Liu 1 and Xiaowei Yu 1 1 Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China * These authors contributed equally to this work and should be considered as equal first coauthors Correspondence to: Xiaowei Yu, email: // Keywords : cordycepin, osteoprotection, oxidative stress, Wnt pathway, Pathology Section Received : August 06, 2015 Accepted : September 28, 2015 Published : October 10, 2015 Abstract Oxidative stress is known to be involved in impairment of osteogenesis and age-related osteoporosis. Cordycepin is one of the major bioactive components of Cordyceps militaris that has been shown to exert antioxidant and anti-inflammatory activities. However, there are few reports available regarding the effects of cordycepin on osteogenesis and the underlying mechanism. In this study, we investigated the potential osteoprotective effects of cordycepin and its mechanism systematically using both in vitro model as well as in vivo mouse models. We discovered that hydrogen peroxide (H 2 O 2 )induced inhibition of osteogenesis which was rescued by cordycepin treatment in human bone marrow mesenchymal stem cells (BM-MSCs) . Cordycepin exerted its protective effects partially by increasing or decreasing expression of osteogenic and osteoclastogenesis marker genes. Treatment with cordycepin increased Wnt-related genes’ expression whereas supplementation of Wnt pathway inhibitor reversed its protective effects. In addition, administration of cordycepin promoted osteogenic differentiation of BM-MSCs by reducing oxidative stress in both ovariectomized and aged animal models. Taken together, these results support the protective effects of cordycepin on oxidative stress induced inhibition of osteogenesis by activation of Wnt pathway.