β-Adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species

Abstract

Sympathetic signaling regulates bone resorption through receptor activator of nuclear factor-B ligand (RANKL) expression via the ␤-adrenergic receptor (␤-AR) on osteoblasts. Reactive oxygen species (ROS) are known as one type of osteoclast regulatory molecule. Here we show that an antioxidant, ␣-lipoic acid (␣-LA), treatment prevent the ␤-adrenergic signaling-induced bone loss by suppressing osteoclastogenesis, and sympathetic signaling directly regulates osteoclastogenesis through ␤2-AR expressed on osteoclasts via intracellular ROS generation. In an in vitro study, the ␤-AR agonist isoprenaline increased intracellular ROS generation in osteoclasts prepared from bone marrow macrophages (BBMs) and RAW 264.7 cells. Isoprenaline enhanced osteoclastogenesis through ␤2-AR expressed on BMMs and RAW 264.7 cells. The antioxidant ␣-LA inhibited isoprenaline-enhanced osteoclastogenesis. Isoprenaline increased the expression of osteoclastrelated genes such as nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1, tartrate-resistant acid phosphatase, and cathepsin K on osteoclasts. ␣-LA also inhibited isoprenaline-induced increases of these gene expressions. These in vitro results led to the hypothesis that ␤-adrenergic signaling directly stimulates osteoclastogenesis via ROS generation. In an in vivo study, isoprenaline treatment alone caused oxidative damage in local bone and reduced bone mass because of an increase in bone resorption, and, in ␣-LAtreated mice, isoprenaline did not increase tibial osteoclast number even though the RANKL-to-osteoprotegerin ratio increased. These in vitro and in vivo results indicate that ␤-adrenergic signaling, at least in part, directly stimulates osteoclastogenesis through ␤2-AR on osteoclasts via ROS generation.␤-adrenergic receptor; bone metabolism; osteoclast THE SYMPATHETIC NERVOUS SYSTEM has been shown to be involved in the regulation of bone remodeling (3,

Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases

“…This was primarily due to the βAR activation on osteoblasts leading to elevated levels of RANKL [129]. These findings are in agreement with studies illustrating the direct effects of βAR stimulation on osteoclastogenesis via reactive oxidase species [130]. Activation of βAR can also impact prostate cancer cells by inhibiting apoptosis and increasing migration in vitro.…”

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

“…In contrast to our study and in support of earlier studies, Aitken et al showed that β2-AR stimulation enhanced osteoclastogenesis indirectly as well as directly [115,116]. Work by Kondo et al demonstrated that the osteoclastogenic effect of β2-AR stimulation was at least partly mediated by induction of reactive oxygen species [117]. These conflicting observations might be due to different stimulation regimen which addressed early and late stage differentiation of osteoclasts comparable to the aforementioned differential effects of SP on early and late stage osteoblastogenesis.…”

Beta-1 Adrenergic Agonist Treatment Mitigates Negative Changes in Cancellous Bone Microarchitecture and Inhibits Osteocyte Apoptosis during Disuse

“…A second limitation is the lack of immunohistochemistry analyses of beta1AR and beta2AR expression in osteoblasts and osteoclasts within weightbearing bone in this study. Previous investigations have determined that human periosteal and rodent osteoblasts express both beta1AR and beta1AR, although the majority of research demonstrates beta2AR to be the primary receptor expressed in osteoblasts [25], [32], [33], [34], [35]. However, to our knowledge it has yet to be determined whether beta1AR are expressed in osteocytes.…”