Interplay between BMPs and Reactive Oxygen Species in Cell Signaling and Pathology

Cristina Sánchez-de-Diego, José Antonio Valer, Carolina Pimenta-Lopes, José Luis Rosa, Francesc Ventura, Cristina Sánchez-de-Diego, José Antonio Valer, Carolina Pimenta-Lopes, José Luis Rosa, Francesc Ventura

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.

Keywords: BMP; MAPK; NOX; NRF2; PI3K; SMAD; cell signaling; reactive oxygen species (ROS).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
BMP signaling pathways. Once BMP receptors (BMPR) are stimulated they form a complex and initiate an intracellular transduction cascade. In the canonical pathway, BMP receptors phosphorylate and activate the SMAD family of transcription factors that transduce the signal to the nucleus. Besides SMADs, BMPs modulate other intracellular signaling pathways (non-canonical BMP signaling) including PI3K/AKT and various types of MAPKs pathways.
Figure 2
Figure 2
ROS-mediated cellular signaling. ROS are highly reactive molecules that act as second messengers inside the cell. Besides mitochondrial respiration, NOXs represent the major ROS source. Under physiological conditions, intracellular ROS target and stimulate several transductor proteins NF-κB, MAPKs, KEAP1-NRF2 and PI3K-AKT important for cell survival, proliferation and differentiation.
Figure 3
Figure 3
Interplay between BMPs and ROS signaling. Production of BMPs and ROSs are reciprocally regulated. BMPs stimulate ROS production by activation and/or induction of NOX1-5 expression while ROS regulate the expression of several BMPs. Furthermore, both BMPs and ROS activate several common signaling pathways including PI3K-AKT, ERK, JNK and p38 MAPKs.
Figure 4
Figure 4
Coordinated contribution of ROS and BMPs to vascular diseases. Vascular vessels are structures integrated by endothelial, smooth muscle cells (SMCs) and fibroblasts. In the endothelium, ROS are mainly produced by NOXs and its levels increase as a response to high pressure. In vascular vessels, ROS induce the expression of several BMPs, inactivates nitric oxide, and stimulate NF-κB pathway. By its part, BMPs activate MAPK pathways, increase NOX1/4 and COX2 expression and consequently enhance ROS generation. BMP6 and oxidized low-density lipoprotein (oxLDL) increase the expression of the osteoblast markers Osterix and Osteopontin in a NOX dependent manner. In SMCs, BMPs promotes the expression of the type III sodium-dependent phosphate cotransporter PIT1, increases the activity of NOX, and the levels of osteogenic markers (RUNX2 and ALPL).

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