Elucidation of molecular mechanism involved in mechanical stress signaling in bone - functional analysis, contribution to pathology, and cloning of related molecule of a novel gene Znt5 -

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We recently isolated a novel gene Znt5 whose expression increased in response to expansion load of rabbit aorta. Znt5 functions as a zinc transporter and Znt5^<-/-> mice exhibited slight growth retardation and osteoporosis as compared to wild-type (WT) littermates. The bone loss seemed to be due to a dysfunction of osteoblasts. To learn the involvement of this molecule in the mechanical stress signaling in bone, we first examined the expression in bone responding to mechanical stress using several models. When three kinds of osteoblastic cell lines, MC3T3-E1,MLO-Y4 and MLO-A5,were cultured with stretching stimulation by the Flexor Cell system, about 2-fold increase of Znt5 expression was seen only in MLO-Y4 cells that are known to be the most differentiated osteoblasts. When three kinds of osteoblastic cell lines, MC3T3-E1,MLO-Y4 and MLO-A5,were cultured with stretching stimulation by the Flexor Cell system, about 2-fold increase of Znt5 expression was seen only in MLO-Y4 cells that ar … More e known to be the most differentiated osteoblasts. In the culture of mouse newborn calvariae, Znt5 expression was induced by continuous tensile stress by an inserted spring for 9 h. In the mouse tail suspension model, Znt5 mRNA level in tibiae and femora was decreased to about one third that of control after 3 weeks of unloading, and was restored to the normal level by reloading. When Znt5^<-/-> mice were treated with tail suspension for 3 weeks, the decrease in bone density (-5%) was much less than that in WT (-15%). In a tibial fracture model and an experimental knee OA model, fracture healing and cartilage destruction, respectively, was similarly seen in WT and Znt5^<-/-> mice. To explore the downstream signaling of Znt5,we compared the gene expression profile between Znt5^<-/-> and WT bones, and found that about 20 genes were decreased in Zn5^<-/->. However, real-time PCR analyses of those mRNA expressions revealed no significant differences between Znt5^<-/-> and WT. We conclude that Znt5, whose expression is positively regulated by mechanical stress in mature osteoblasts or osteocytes, plays an essential role in the maintenance of bone volume by mechanical stress. Less