Recent studies demonstrate that diet quercetin (Quer) has obvious bone protective effects on ovariectomized rodents but thus far there is no direct evidence to support the inhibitory effect of Quer on bone loss caused by long-term unloading.In the present study,we investigated whether Quer could prevent bone loss induced by unloading in mice.Mice were subjected to hindlimb suspension (HLS) and received Quer (25,50,100 mg· kg-1 ·day-1,ig) for 4 weeks.Before euthanasia blood sample was collected;the femurs were harvested and subjected to MicroCT analysis.We showed that Quer administration markedly improved bone microstructure evidenced by dose-dependently reversing the reduction in bone volume per tissue volume,trabecular number,and bone mineral density,and the increase of trabecular spacing in mice with HLS.Analysis of serum markers and bone histometric parameters confirmed that Quer at both middle and high doses significantly decreased bone resorption-related markers collagen type Ⅰ and tartrate-resistant acid phosphatase 5b,and increased bone formation-related marker procollagen 1 N-terminal propeptide as compared with HLS group.Treatment with Quer (1,2,5 μM) dose-dependently inhibited RANKL-induced osteoclastogenesis through promoting the expression of antioxidant hormone stanniocalcin 1 (STC1) and decreasing ROS generation;knockdown of STC1 blocked the inhibitory effect of Quer on ROS generation.Knockdown of STC1 also significantly promoted osteoclastogenesis in primary osteoclasts.In conclusion,Quer protects bones and prevents unloading-caused bone loss in mice through STC1-mediated inhibition of osteoclastogenesis.The findings suggest that Quer has the potential to prevent and treat off-load bone loss as an alternative supplement.