Editors' ChoiceBone Biology

Building Bone with Nuclear Oxytocin Receptors

Science Signaling  25 Nov 2014:
Vol. 7, Issue 353, pp. ec327
DOI: 10.1126/scisignal.aaa3398

Oxytocin is a hormone that activates a G protein–coupled receptor (GPCR) to mediate social bonding, stimulate lactation, and promote bone formation. Di Benedetto et al. found that the addition of oxytocin to primary mouse osteoblasts or a preosteoblastic cell line stimulated the internalization and nuclear accumulation of the oxytocin receptor (Oxtr), a result observed by immunofluorescence confocal microscopy, immunogold electron microscopy, and subcellular fractionation. Monitoring the movement and colocalization of an enhanced green fluorescent protein (EGFP)–tagged Oxtr in osteoblasts from Oxtr-/- mice showed the sequential movement of EGFP-Oxtr from the plasma membrane to endocytic vesicles, transient colocalization with the adaptor protein arrestin, and finally accumulation in the inner nuclear membrane and colocalization with the importin protein Tnpo1. Knockdown of arrestin 1, arrestin 2, or Tnpo1 inhibited oxytocin-induced expression of osteoblast differentiation genes without reducing oxytocin-induced phosphorylation of extracellular signal–regulated kinase (ERK). Similarly, introducing Oxtr with mutations in serine residues necessary for the interaction with arrestins into the Oxtr-/- osteoblasts blocked oxytocin-mediated activation of gene expression without affecting ERK phosphorylation. Thus, the GPCR Oxtr appears to signal from the nucleus to stimulate an osteoblast differentiation transcriptional response.

A. Di Benedetto, L. Sun, C. G. Zambonin, R. Tamma, B. Nico, C. D. Calvano, G. Colaianni, Y. Ji, G. Mori, M. Grano, P. Lu, S. Colucci. T. Yuen, M. I. New, A. Zallone, M. Zaidi, Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor. Proc. Natl. Acad. Sci. U.S.A. 111, 16502–16507 (2014). [Abstract] [Full Text]