Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and
Reverses Osteoporosis
Christian Elabd 1, Armelle Basillais 2, Hélène Beaupied 2, Véronique
Breuil 3, Nicole Wagner 4, Marcel Scheideler 5, Laure Emmanuelle
Zaragosi 1, Florence Massiéra 1, Emmanuel Lemichez 6, Zlatko
Trajanoski 4, Georges Carle 7, Liana Euller-Ziegler 8, Gérard Ailhaud
1, Claude Laurent Benhamou 2, Christian Dani 1, Ez Zoubir Amri 1*
1 ISBDC, Université de Nice Sophia-Antipolis, CNRS; 28 avenue de
Valrose, 06100 Nice, France
2 INSERM U 658, IPROS Hopital Porte Madeleine BP 2439, 45032 Orléans
Cedex 1, France
3 GEPITOS, Université de Nice Sophia-Antipolis, CNRS; Faculté de
Médecine, IFR50, Avenue de Valombrose, 06107 Nice Cedex 2, France;
Service de Rhumatologie, CHU l'Archet 1, BP79, 06200 Nice Cedex 3,
France
4 INSERM U907, Faculté de Médecine, 28 Avenue de Valombrose 06107,
Nice Cedex 2, France
5 Institute for Genomics and Bioinformatics, Graz University of
Technology, Graz, Austria
6 INSERM U627, Faculté de Médecine, 28 Avenue de Valombrose, 06107,
Nice, Cedex 2, France.
7 GEPITOS, Université de Nice Sophia-Antipolis, CNRS; Faculté de
Médecine, IFR50, Avenue de Valombrose, 06107 Nice Cedex 2, France
8 Service de Rhumatologie, CHU l'Archet 1, BP79, 06200 Nice Cedex 3,
France
* To whom correspondence should be addressed. E-mail: amri@unice.fr.
Abstract
Osteoporosis constitutes a major worldwide public health burden
characterized by enhanced skeletal fragility. Bone metabolism is the
combination of bone resorption by osteoclasts and bone formation by
osteoblasts. While increase in bone resorption is considered as the
main contributor of bone loss that may lead to osteoporosis, this
loss is accompanied by increased bone marrow adiposity. Osteoblasts
and adipocytes share the same precursor cell and an inverse
relationship exists between the two lineages. Therefore, identifying
signaling pathways that stimulates mesenchymal stem cells
osteogenesis at the expense of adipogenesis is of major importance in
order to develop new therapeutic treatments. For this purpose, we
identified by transcriptomic analysis the oxytocin receptor pathway
as a potential regulator of the osteoblast/adipocyt
multipotent adipose-derived stem (hMADS) cells. Both oxytocin (OT)
and carbetocin (Cb, a stable OT analogue) negatively modulate
adipogenesis while promoting osteogenesis in both hMADS cells and
human bone marrow mesenchymal stromal cells (hBMSC). Consistent with
these observations ovariectomized (OVX) mice and rats, which become
osteoporotic and exhibit disequilibrium of this balance, have
significant decreased OT levels compared to sham-operated controls.
Subcutaneous OT injection reverses bone loss in OVX mice and reduces
marrow adiposity. Clinically, plasma OT levels are significantly
lower in postmenopausal women developing osteoporosis than in their
healthy counterparts. Taken together, these results suggest that
plasma OT levels represent a novel diagnostic marker for osteoporosis
and that OT administration holds promise as a potential therapy for
this disease.
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