Leptin regulation of bone resorption by the sympathetic nervous system and CART

Abstract

Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.

Deletion of β-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation

“…These observations strongly contrast with Adrb2 À/À mice, which do not present a bone phenotype during growth and develop a higher trabecular bone volume by about 6 months of age. (14) Here we also confirm the high vertebral bone mass phenotype of Adrb2 À/À mice and further demonstrate that, contrarily to Adrb1 À/À and Adrb1b2 À/À mice, the anabolic response of the peripheral skeleton to axial compression is not altered in Adrb2 À/À mice. The concomitant absence of b1-and b2-adrenergic signaling leads to low bone mass and low cancellous and cortical microarchitecture.…”

“…(12,13) Adrenergic agonists stimulated bone resorption in neonatal mouse calvariae, (10) increased osteoclastogenesis in vitro, and promoted the osteoblastic production of interleukin 6 (IL-6) and receptor activator of NF-kB ligand (RANKL)-two osteoclast-activating cytokines. (14,15) In turn, b2-adrenergic receptor deficient (Adrb2 À/À ) mice were characterized by increased cancellous bone volume and bone formation rate (BFR) compared to their wild-type (WT) as they age (ie, by 6 months of age) and also following estrogen-deficiency, at least when ovariectomy was performed during growth (ie, by 1 month of age). (14) Thus, b2-adrenergic signaling directly inhibits bone formation and promotes osteoclastogenesis by increasing RANKL.…”

“…(14,15) In turn, b2-adrenergic receptor deficient (Adrb2 À/À ) mice were characterized by increased cancellous bone volume and bone formation rate (BFR) compared to their wild-type (WT) as they age (ie, by 6 months of age) and also following estrogen-deficiency, at least when ovariectomy was performed during growth (ie, by 1 month of age). (14) Thus, b2-adrenergic signaling directly inhibits bone formation and promotes osteoclastogenesis by increasing RANKL. (16) In contrast, we reported that obese b-less mice (deletion of b1-, b2-, and b3-adrenergic receptors) are not protected against cancellous bone loss during aging and with ovariectomy, suggesting that concomitant loss of b1-adrenergic receptors and/or b3-adrenergic receptors may counteract the protective effects of b2-adrenergic receptor deficiency.…”

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

“…Most of the literature supports the idea that leptin suppresses bone mass by acting in the brainstem to reduce serotonin-dependent sympathetic signaling from the ventromedial hypothalamus to bone. Osteoblasts appear to be a target of this central regulation and lead to reduced bone formation and increased expression of RANKL that promotes osteoclast differentiation and bone resorption [38,39]. In our study, a relatively strong correlation has been established between increased adiponectin and reduced leptin levels, and increased trabecular bone volume indicating that the modifications of adipokine profile in GIPR-deficient animals could result in the observed bone phenotype.…”

Cilnidipine, but not amlodipine, ameliorates osteoporosis in ovariectomized hypertensive rats through inhibition of the N-type calcium channel

“…20,36,37 Bone and its periosteum receive a rich supply of sensory and sympathetic nerves, 38 suggesting the neuroendocrine regulation of bone remodeling. Both osteoblasts and osteoclasts possess a1 and a2 and/or b2-adrenergic receptors, and adrenergic stimulation from sympathetic nerves enhanced bone resorption.…”