Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis

Elabd, Christian; Basillais, A.; Beaupied, Hélène; Breuil, Véronique; Wagner, Nicole; Scheideler, Marcel; Zaragosi, Laure‐Emmanuelle; Massiéra, Florence; Lemichez, Emmanuel; Trajanoski, Zlatko; Carle, Georges F.; Euller‐Ziegler, Liana; Ailhaud, Gérard; Benhamou, Claude Laurent; Dani, Christian; Amri, Ez-Zoubir

doi:10.1634/stemcells.2008-0127

Cited by 176 publications

(212 citation statements)

References 75 publications

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“…Furthermore, several agents or stimuli exert the anabolic effect with this mechanism. 2,3,26 In the current study, the greater bone volume after Sr treatment was accompanied with an increased osteogenic and decreased adipogenic potential of BMSCs by ex vivo study. Considering that Sr can increase osteogenic differentiation of murine or human BMSCs in vitro, 11,12 the in vivo anabolic effect of Sr may at least partially be attributed to the favorable differentiation of osteoblast lineage.…”

Section: Discussionsupporting

confidence: 50%

In vivo anabolic effect of strontium on trabecular bone was associated with increased osteoblastogenesis of bone marrow stromal cells

Peng

Liu

Wang

et al. 2010

Journal Orthopaedic Research

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ABSTRACT:In vitro studies have demonstrated that strontium (Sr) could increase osteogenic differentiation of bone marrow stromal cells (BMSCs). We investigated the in vivo effect of Sr on BMSCs. Thirty-six female rats were randomly divided into the following groups: sham operated and treated with either vehicle (Sham þ Veh) or Sr compound (Sham þ Sr) and ovariectomized and treated with either vehicle (OVX þ Veh) or Sr compound (OVX þ Sr). Vehicle and Sr were orally administrated daily starting immediately after the surgery and continuing for 12 weeks. The anabolic effect of Sr on trabecular bone was determined at the structural and tissue level by microCT and histomorphometry, respectively. Colony formation assays demonstrated that BMSCs exhibited higher osteogenic colony but lower adipogenic colony in Sr-treated versus Veh-treated OVX rats. The mRNA level of osteogenic genes was higher, while the mRNA level of adipogenic genes was lower in BMSCs from Sr-treated versus Veh-treated Sham and OVX rats. The effect of Sr on rat BMSCs was reproducible in human BMSCs. Taken together, this study suggests that the anabolic effect of Sr on normal or osteoporotic bones is associated with increased osteoblastic differentiation of BMSCs. Keywords: strontium; osteoblastogenesis; adipogenesis; bone marrow stromal cells; osteoporosis Bone marrow stromal cells (BMSCs) can differentiate into a number of lineages, including osteoblasts, chondroblasts, and adipocytes. 1 This multipotent differentiation potential makes them good candidates to regenerate degenerating tissues and restore their function. Recent studies suggest that low magnitude mechanical signals can increase bone volume and reduce fat tissues in male mice by stimulating BMSCs proliferation and differentiation into an osteoblast lineage. 2 Moreover, Bortezomib (Bzb), a first-in-class proteasome inhibitor used to treat myeloma patients, exerts an anabolic effect on bone by stimulating the differentiation of BMSCs into osteoblasts, thus leading to new bone formation. 3 These studies indicate that modulation of in vivo lineage differentiation of BMSCs is a feasible approach to build bone volume, which may serve as a new strategy to treat postmenopausal osteoporosis.Strontium ranelate (SR), a new anti-osteoporosis agent, can decrease vertebral and nonvertebral fracture risks in postmenopausal women. [4][5][6] Previous studies on postmenopausal women showed that the serum bone formation marker was increased due to SR treatment as compared to placebo controls. 4 In OVX rats, SR treatment prevented bone loss by increasing the bone formation maker and decreasing the bone resorption marker. 7,8 The cellular and molecular mechanism of the anabolic effect of strontium (Sr) on bone remains poorly understood. In vitro studies suggest that Sr can promote osteoblast proliferation and differentiation. 9,10 Recent studies also demonstrated that Sr can increase in vitro osteogenic differentiation of BMSCs. 11,12 Based on the observation that Sr could increase osteoblastic differentiati...

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Section: Discussionsupporting

confidence: 50%

In vivo anabolic effect of strontium on trabecular bone was associated with increased osteoblastogenesis of bone marrow stromal cells

Peng

Liu

Wang

et al. 2010

Journal Orthopaedic Research

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“…This anabolic action has been documented in both wild-type mice (Fig. S1) and ovariectomized mice (26).…”

Section: Resultsmentioning

confidence: 53%

Oxytocin is an anabolic bone hormone

Tamma

Colaianni

Zhu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

231

289

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We report that oxytocin (OT), a primitive neurohypophyseal hormone, hitherto thought solely to modulate lactation and social bonding, is a direct regulator of bone mass. Deletion of OT or the OT receptor (Oxtr) in male or female mice causes osteoporosis resulting from reduced bone formation. Consistent with low bone formation, OT stimulates the differentiation of osteoblasts to a mineralizing phenotype by causing the up-regulation of BMP-2, which in turn controls Schnurri-2 and 3, Osterix, and ATF-4 expression. In contrast, OT has dual effects on the osteoclast. It stimulates osteoclast formation both directly, by activating NF-B and MAP kinase signaling, and indirectly through the up-regulation of RANK-L. On the other hand, OT inhibits bone resorption by mature osteoclasts by triggering cytosolic Ca 2؉ release and NO synthesis. Together, the complementary genetic and pharmacologic approaches reveal OT as a novel anabolic regulator of bone mass, with potential implications for osteoporosis therapy.osteoblast ͉ osteoclast ͉ osteoporosis ͉ pituitary hormones ͉ bone density O xytocin (OT), a hypothalamic nanopeptide secreted into the circulation from the posterior pituitary, is indispensable for lactation. It acts on a G protein-coupled receptor (Oxtr), the expression of which in reproductive tissues is regulated by sex steroids and OT. In humans and rodents, plasma OT levels are elevated maximally during suckling (1, 2).Mice lacking OT or its receptor (Oxtr) are unable to lactate, despite unperturbed breast tissue and milk formation (3, 4). Most notably, newborn pups die shortly after birth in the absence of a foster mother postpartum. This effect of OT is exerted peripherally, as the i.p. administration of recombinant OT to OT Ϫ/Ϫ mice rescues milk ejection, allowing the newborn to feed normally. In contrast to the milk ejection defect, no deficits in copulation, gestation, fecundity, or parturition have been noted in either OT Ϫ/Ϫ or Oxtr Ϫ/Ϫ mice, suggesting that these mice are typically eugonadal (5). Furthermore, compound mutants with both the Oxtr and the prostaglandin F2␣ receptor deleted exhibit no defects in parturition, indicating significant redundancy in the birth process per se (5). However, in view of the established pharmacology of circulating OT on the uterine myometrium, the possibility of a physiological action of OT during childbirth cannot be excluded, even without a loss-of-function phenotype.Two other key actions of OT warrant mention: effects on social , behavior and on the regulation of food intake. Male OT Ϫ/Ϫ and Oxtr Ϫ/Ϫ mice show deficits in social recognition, without altered cognition or olfactory learning. That this social amnesia is a central rather than a peripheral action of OT is supported by the observation that recombinant OT injected directly into the amygdala rescues the defect (6). Compared with males, female OT or Oxtr null mice display anxiety and exaggerated stress responses, which are likewise mediated through central OT-ergic neurones (7). OT also is involved in the reg...

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“…Consistent with this, plasma oxytocin levels are significantly lower in osteoporotic postmenopausal women compared with non-osteoporotic women (129). Such bone loss can be inhibited by administration of oxytocin in a mouse model of osteoporosis (129).…”

Section: Osteoporosissupporting

confidence: 60%

Oxytocin: recent developments

Tom

Assinder

2010

BioMolecular Concepts

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Oxytocin is a neurohypophyseal hormone that is produced centrally by neurons in the paraventricular nucleus and supraoptic nucleus of the hypothalamus. It is released directly into higher brain centres and into the peripheral circulation where it produces a multitude of effects. Classically, oxytocin is known for inducing uterine contractions at parturition and milk ejection during suckling. Oxytocin also acts in a species and gender specific manner as an important neuromodulator. It can affect behaviours associated with stress and anxiety, as well social behaviours including sexual and relationship behaviours, and maternal care. Additionally, oxytocin has been shown to have a variety of physiological roles in peripheral tissues, many of which appear to be modulated largely by locally produced oxytocin, dispelling the notion that oxytocin is a purely neurohypophyseal hormone. Oxytocin levels are altered in several diseases and the use of oxytocin or its antagonists have been identified as a possible clinical intervention in the treatment of mood disorders and pain conditions, some cancers, benign prostatic disease and osteoporosis. Indeed, oxytocin has already been successful in clinical trials to treat autism and schizophrenia. This review will report briefly on the known functions of oxytocin, it will discuss in depth the data from recent clinical trials and highlight future targets for oxytocinergic modulation.

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Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis

Cited by 176 publications

References 75 publications

In vivo anabolic effect of strontium on trabecular bone was associated with increased osteoblastogenesis of bone marrow stromal cells

In vivo anabolic effect of strontium on trabecular bone was associated with increased osteoblastogenesis of bone marrow stromal cells

Oxytocin is an anabolic bone hormone

Oxytocin: recent developments

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