BackgroundMechanical unloading induces bone loss in human weight-loaded bones. The findings of recent studies have revealed that cluster of differentiation 38 knockout mice display bone loss similar to that observed in osteoporosis. This study aimed to determine whether the expression of cluster of differentiation 38 is implicated in skeletal unloading and reloading. MethodsEight-week-old male C57BL/6J mice were assigned to control, tail-suspension, or reloading after tail-suspension groups. In the tail-suspension group, tail suspension elevated the hind limbs for 1 week. The bilateral femurs and tibias from the groups were evaluated for cluster of differentiation 38 immunocytochemistry, and the cluster of differentiation 38 messenger ribonucleic acid levels and the expression of cluster of differentiation 38 and other cell-surface antigens were evaluated using quantitative real-time polymerase chain reaction and flow cytometric analyses. ResultsIn the tail-suspension group, the alkaline phosphatase reactivity, cluster of differentiation 38 immunoreactivity in the bone marrow and osteoblasts, and the expression of cluster of differentiation 38 messenger ribonucleic acid and that of other cell-surface antigens were significantly lower than those in the control group. In the reloading after tail-suspension group, the level of cluster of differentiation 38 expression was restored to the same level as that in the control group. ConclusionsCluster of differentiation 38 expression declined after skeletal unloading and recovered to normal levels after reloading. In the bone marrow, cluster of differentiation 38 expression plays a crucial role in bone formation in response to mechanical stress.