Oxytocin is an anabolic bone hormone

Abstract

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...

Functions of vasopressin and oxytocin in bone mass regulation

“…osteoporosis | osteoblast | skeleton O ver the past decade, we have described direct actions of anterior and posterior pituitary hormones on the skeleton (1)(2)(3)(4)(5)(6)(7)(8). We have shown that these actions are exerted via G protein-coupled receptors resident on both osteoblasts and osteoclasts.…”

Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor

“…However, this effect is in contrast to uterine myocytes, wherein pErk is reduced in mice lacking either Arrb1 or Arrb2 (26). The intactness of the pErk response in osteoblasts could be explained by the known activation of MAPKs by G αi and G αq (28); this actin could account for the positive effect of Oxt on osteoblast viability that we have shown earlier (4).…”

“…We have shown previously that osteoblasts express abundant plasma membrane Oxtrs that drive cell differentiation to a mature, mineralizing phenotype in response to pituitary-and bone marrow-derived Oxt (4,6). However, the mechanism of this effect has remained uncertain.…”

“…Oxtrs are present on osteoclast precursors and osteoclasts (36), and their stimulation results in increased osteoclastogenesis but inhibited bone resorption (4). Rapid rises in Oxt during periods of calcium stress (1) might enable calcium mobilization followed by the rapid cessation of bone resorption through a brake on active osteoclasts (4).…”

“…More recently, we and others have shown that Oxt also stimulates bone formation directly by interacting with an osteoblastic Oxtr (3,4). The genetic deletion of Oxt or Oxtr in mice thus decreases osteoblast differentiation and bone formation, causing osteopenia (5,6).…”