Bone Marrow Oxytocin Mediates the Anabolic Action of Estrogen on the Skeleton

Graziana Colaianni,Concetta Cuscito,Jianhua Li,Katsuhiko Nishimori,Tony Yuen,Mone Zaidi,Roberto Tamma,Alberta Zallone,Jay Cao,Jameel Iqbal,Itai Bab,Adriana Di Benedetto,Li Sun,Maria Grano,Heon-Jin Lee,Simona Colucci ,W Scott Young ,Clifford J Rosen ,L Mancini ,Ling Zhu

doi:10.1074/jbc.m112.365049

Abstract

Estrogen uses two mechanisms to exert its effect on the skeleton: it inhibits bone resorption by osteoclasts and, at higher doses, can stimulate bone formation. Although the antiresorptive action of estrogen arises from the inhibition of the MAPK JNK, the mechanism of its effect on the osteoblast remains unclear. Here, we report that the anabolic action of estrogen in mice occurs, at least in part, through oxytocin (OT) produced by osteoblasts in bone marrow. We show that the absence of OT receptors (OTRs) in OTR(-/-) osteoblasts or attenuation of OTR expression in silenced cells inhibits estrogen-induced osteoblast differentiation, transcription factor up-regulation, and/or OT production in vitro. In vivo, OTR(-/-) mice, known to have a bone formation defect, fail to display increases in trabecular bone volume, cortical thickness, and bone formation in response to estrogen. Furthermore, osteoblast-specific Col2.3-Cre(+)/OTR(fl/fl) mice, but not TRAP-Cre(+)/OTR(fl/fl) mice, mimic the OTR(-/-) phenotype and also fail to respond to estrogen. These data attribute the phenotype of OTR deficiency to an osteoblastic rather than an osteoclastic defect. Physiologically, feed-forward OT release in bone marrow by a rising estrogen concentration may facilitate rapid skeletal recovery during the latter phases of lactation.

Highlights

The mechanism underlying the anabolic effect of estrogen on the skeleton is unclear
We report that estrogen-induced bone formation in mice occurs through oxytocin (OT) produced by osteoblasts in bone marrow
We report that the anabolic action of estrogen in mice occurs, at least in part, through oxytocin (OT) produced by osteoblasts in bone marrow

Summary

Conclusion

Feed-forward OT release in bone marrow by a rising estrogen level may facilitate rapid skeletal recovery after lactation. In line with its peripheral effect, we found that osteoblasts possess abundant OT receptors (OTRs) and that OT triggers osteoblast differentiation to a mature mineralizing phenotype [6] Consistent with this anabolic action, the genetic deletion of OT or the OTR in mice decreases osteoblast differentiation and bone formation, resulting in osteopenia [6]. The increased bone formation noted normally during pregnancy is attenuated in OTϪ/Ϫ mice, as is fetal skeletal mineralization in OTϪ/Ϫ pups [8] Together, these findings suggest that the anabolic action of OT may, facilitate maternal skeletal recovery and fetal skeletogenesis. We postulate that an autocrine feed-forward OT/OTR loop exists in which estrogen releases OT from osteoblasts, which acts upon osteoblastic OTRs to further amplify estrogen action This could be advantageous for maternal skeletal replenishment during the postpartum period, when estrogen levels are returning to normal and OT is high [19]

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION