Abstract
The integration of cell extrinsic and intrinsic signals is required to maintain appropriate cell physiology and homeostasis. Bone morphogenetic proteins (BMPs) are cytokines that belong to the transforming growth factor-β (TGF-β) superfamily, which play a key role in embryogenesis, organogenesis and regulation of whole-body homeostasis. BMPs interact with membrane receptors that transduce information to the nucleus through SMAD-dependent and independent pathways, including PI3K-AKT and MAPKs. Reactive oxygen species (ROS) are intracellular molecules derived from the partial reduction of oxygen. ROS are highly reactive and govern cellular processes by their capacity to regulate signaling pathways (e.g., NF-κB, MAPKs, KEAP1-NRF2 and PI3K-AKT). Emerging evidence indicates that BMPs and ROS interplay in a number of ways. BMPs stimulate ROS production by inducing NOX expression, while ROS regulate the expression of several BMPs. Moreover, BMPs and ROS influence common signaling pathways, including PI3K/AKT and MAPK. Additionally, dysregulation of BMPs and ROS occurs in several pathologies, including vascular and musculoskeletal diseases, obesity, diabetes and kidney injury. Here, we review the current knowledge on the integration between BMP and ROS signals and its potential applications in the development of new therapeutic strategies.
Highlights
Bone morphogenetic proteins (BMPs) were first described in the 1960s as osteoinductive soluble factors that belong to the transforming growth factor-β (TGF-β) superfamily [1]
NOX1-5 expression while reactive oxygen species (ROS) regulate the expression of several BMPs
Evidence supports that both signals influence each other: BMP-dependent regulation of ROS production, and vice-versa, increases in the expression of distinct BMPs or modification on the expression of BMP antagonists in response to ROS
Summary
Bone morphogenetic proteins (BMPs) were first described in the 1960s as osteoinductive soluble factors that belong to the transforming growth factor-β (TGF-β) superfamily [1]. The information is transduced to the nucleus through the SMAD pathway Besides this signaling mode, several non-canonical, SMAD-independent BMP transducers have been identified, including small GTPases, phosphatidylinositol 3-kinase/AKT (PI3K/AKT) and distinct types of mitogen-activated protein kinases (MAPKs) [16]. Several non-canonical, SMAD-independent BMP transducers have been identified, including small GTPases, phosphatidylinositol 3-kinase/AKT (PI3K/AKT) and distinct types of mitogen-activated protein kinases (MAPKs) [16] In this context, recent evidence suggests that reactive oxygen species (ROS) can act as second messengers for BMPs. ROS are highly reactive molecules derived from the reduction of molecular oxygen as a consequence of cellular metabolism or the activity of specific enzymes, such as the NADPH oxidase (NOX). We will describe the putative modes of signaling crosstalk between BMPs and ROS and analyze their implications in physiology and disease
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