Functions of vasopressin and oxytocin in bone mass regulation

Abstract

Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr −/− mice have osteopenia, and Avpr1α −/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr −/− :Avpr1α −/− doublemutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avpstimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α −/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.O ver the past decade, we have described direct actions of anterior and posterior pituitary hormones on the skeleton (1-8). We have shown that these actions are exerted via G protein-coupled receptors resident on both osteoblasts and osteoclasts. We also find that the skeleton is highly sensitive to the action of posterior pituitary hormones; for example, mice haploinsufficient in oxytocin (Oxt) have osteopenic bones, but lactation is normal; lactation is impaired only in Oxt −/− mice (2). Likewise, Tshr haploinsufficient mice are completely euthyroid with normal thyroid follicles but display significant osteopenia (4). The exquisite sensitivity of the skeleton to pituitary hormones comes as no surprise, considering that the pituitary gland and the skeleton are both evolutionarily more primitive than target endocrine organs (7).Apart from the known actions of growth hormone on the skeleton, Tsh, Fsh, Acth, Oxt, and vasopressin (Avp) have all been shown to regulate the formation and/or function of both osteoblasts and osteoclasts and thus to control bone remodeling in vivo (2-4, 6-8). The two neurohypophyseal hormones Oxt and Avp have opposing functions (2, 3). Oxt stimulates and Avp inhibits osteoblast formation. Consequently, the genetic deletion of the Oxt receptor (Oxtr) and Avp receptor 1α (Avpr1α) yields opposing phenotypes, notably osteopenia in Oxtr −/− mice and high bone mass in Avpr1α −/− mice (2, 3). These findings may explain the rapid recovery of bone loss at weaning when plasma Oxt levels are high (9) and also the profound loss of bone noted in chronic hyponatremic states, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in which serum Avp levels are elevated (3).We find high levels of Oxtr expression on ...

Pituitary-bone connection in skeletal regulation

“…This high bone mass phenotype was also observed in AVPR1A-deficient mice [111]. In contrast, AVPR2 does not have a significant role in bone remodeling, since the specific AVPR2 inhibitor tolvaptan does not affect bone formation or bone mass [112]. Collectively, the data establish a primary role for AVP signaling in bone mass regulation.…”

“…AVPR1A and OXTR have opposing effects on bone mass. Notably, the deletion of OXTR in OXTR -/-:AVPR1A -/-double-mutant mice reversed the high bone mass phenotype in AVPR1A -/-mice [112]. While OXTR deletion in AVPR1A -/-cells inhibits AVP-stimulated gene expression, OXTR is dispensable for the anti-osteoblastic action of AVP [112].…”

“…While OXTR deletion in AVPR1A -/-cells inhibits AVP-stimulated gene expression, OXTR is dispensable for the anti-osteoblastic action of AVP [112]. Furthermore, OXT does not interact with AVPRs in vivo in a model of lactation-induced bone loss in which OXT levels are high [112].…”

The endocrine manifestations of anorexia nervosa: mechanisms and management

“…Hyponatraemia is associated with reduced BMD in a rodent model of SIAD 130 , and oxytocin deficiency is also associated with low BMD in oxytocin and oxytocin receptor null mice 131 . Similar to preclinical studies, hyponatraemia 129 is associated with decreased BMD in women with anorexia nervosa independent of BMI; low nocturnal serum oxytocin levels 84 are also associated with decreased BMD.…”

Microbial lysate upregulates host oxytocin

“…Interestingly, many of the published beneficial health effects of oxytocin overlap with recognized L. reuteri health-promoting attributes. Indeed, as with L. reuteri (Britton et al, 2014; Collins et al, 2016; Poutahidis et al, 2013a,b; Varian et al, 2016a,b, 2014; Zhang et al, 2015b), the exogenous administration of oxytocin has been shown to accelerate wound healing (Gavrilenko et al, 2003; Gouin et al, 2010; Vitalo et al, 2009), counteract obesity (Barengolts, 2016; Blevins and Baskin, 2015), suppress uncontrolled inflammation (Wang et al, 2015) and prevent muscle wasting (Costa et al, 2014; Elabd et al, 2014) and bone loss (Colaianni et al, 2014; Sun et al, 2016; Tamma et al, 2009). …”