Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia

Although hyponatremia is known to be associated with osteoporosis and a high fracture risk, the mechanism through which bone loss ensues has remained unclear. As hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, we examined whether AVP can affect the skeleton directly as yet another component of the pituitary-bone axis. Here, we report that the two Avp receptors, Avpr1α and Avpr2, coupled to Erk activation, are expressed in osteoblasts and osteoclasts. AVP injected into wild-type mice enhanced and reduced, respectively, the formation of bone-resorbing osteoclasts and bone-forming osteoblasts. Conversely, the exposure of osteoblast precursors to Avpr1α or Avpr2 antagonists, namely SR49059 or ADAM, increased osteoblastogenesis, as did the genetic deletion of Avpr1α. In contrast, osteoclast formation and bone resorption were both reduced in Avpr1α^−/− cultures. This process increased bone formation and reduced resorption resulted in a profound enhancement of bone mass in Avpr1α^−/− mice and in wild-type mice injected with SR49059. Collectively, the data not only establish a primary role for Avp signaling in bone mass regulation, but also call for further studies on the skeletal actions of Avpr inhibitors used commonly in hyponatremic patients.Over the past decade, studies by others and us have documented direct effects of pituitary hormones on the skeleton. We have identified functional receptors for thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), and oxytocin (OT) on murine and human bone cells, namely bone-forming osteoblasts and bone-resorbing osteoclasts (1–4). The genetic deletion of either the receptor or the ligand itself, as in the case of FSH and OT, results in overt skeletal abnormalities. Specifically, deleting OT or its receptor, the Oxtr, causes profound osteopenia, which primarily arises from a dramatic reduction in bone formation by the osteoblast (4). Such studies have helped establish a pituitary-bone axis, in which pituitary hormones bypass their known targets, such as the thyroid, ovaries, adrenal, and breast, to regulate bone directly (5).This growing body of data not only informs us of novel functions of pituitary hormones, but also explains the hitherto poorly understood mechanisms of certain forms of osteoporosis, which have traditionally been attributed solely to changes in distal hormones. For example, we find that low TSH signaling contributes to the bone loss in hyperthyroidism, which was thought solely to be a result of elevated thyroid hormones (6). We have also speculated that the rapid bone loss that occurs during late perimenopause, at a time when estradiol levels are relatively normal, could—at least in part—be caused by elevated serum FSH levels. Thus, an antibody to FSH reduces bone loss in ovariectomized mice by stimulating bone formation and inhibiting bone resorption (7). Similarly, through its skeletal anabolic actions, elevated OT levels during pregnancy and lactation could play a major role in enabling fetal skeletal mineralization and allowing the mother to recover from the osteoporosis caused by the intergenerational transfer of calcium (8).Here, we report studies on arginine-vasopressin (AVP), another posterior pituitary hormone, which differs from OT only by two amino acids (9). The direct skeletal actions of AVP have never been explored, despite multiple and recurring observations that hyponatremia, which is invariably accompanied by elevated plasma AVP levels, is associated with bone loss and a high fracture risk (10–16). It has been thought that, as bone is a large reservoir for sodium ions, hyponatremia will trigger sodium release from the skeleton by increasing bone resorption (17, 18). However, the molecular basis of any such effect remains unknown. Interestingly, a recent study has described a male patient with syndrome of inappropriate secretion of antidiuretic hormone- (SIADH) induced hyponatremia, who had severe osteoporosis, despite having no identifiable risk factors (19). Plasma AVP was elevated by ∼30-fold, raising the possibility that high circulating AVP levels may cause the profound bone loss.We show that AVP is a key regulator of bone resorption and formation, the two principal components of bone remodeling. Both Avp receptors, Avpr1α and Avpr2, are expressed on osteoclasts and osteoblasts, and their stimulation triggers extracellular signal regulated kinase (Erk) activation, which in turn suppresses bone formation and stimulates bone resorption. This decoupling would favor bone loss, as noted in hyponatremic states. However, we also find that the genetic deletion of Avpr1 or the pharmacologic inhibition of Avpr1 or Avpr2 increases bone mass not only by stimulating osteoblastogenesis and new bone synthesis, but also by simultaneously inhibiting osteoclast formation and bone resorption. We speculate, therefore, that the targeted therapy of hyponatremia with aquaretics (or AVPR inhibitors) could result in overall bone gain. Purposefully designed clinical studies in populations in whom hyponatremia is a significant clinical problem (20), and whom are otherwise also at a high risk for fracture (21), should shed further light on the proposed osteoprotective action of AVPR antagonists in people.