Abstract
The pH of extracellular fluids is a basic property of the tissue microenvironment and is normally maintained at 7.40 ± 0.05 in humans. Many pathological circumstances, such as ischemia, inflammation, and tumorigenesis, result in the reduction of extracellular pH in the affected tissues. In this study, we reported that the osteogenic differentiation of BMSCs was significantly inhibited by decreases in the extracellular pH. Moreover, we demonstrated that proton-sensing GPR4 signaling mediated the proton-induced inhibitory effects on the osteogenesis of BMSCs. Additionally, we found that YAP was the downstream effector of GPR4 signaling. Our findings revealed that the extracellular pH modulates the osteogenic responses of BMSCs by regulating the proton-sensing GPR4-YAP pathway.
Highlights
The microenvironment plays important roles in the maintenance of normal tissue homeostasis and the development of diseases[1,2]
We found that the osteogenic activities of bone marrow-derived mesenchymal stem cells (BMSCs) were decreased with reductions in the extracellular pH and that GPR4-induced suppression of Yes-associated protein (YAP) might be an important mechanism by which proton-induced anti-osteogenic effects are elicited in BMSCs because these effects could be blocked by the inhibition of GPR4 or the activation of YAP
To explore the effects of extracellular pH on the osteogenic differentiation of BMSCs, the cells were cultured in osteogenic medium with different proton concentrations, and alizarin red S staining was performed after 21 days of differentiation
Summary
The microenvironment plays important roles in the maintenance of normal tissue homeostasis and the development of diseases[1,2]. Inflammation, ischemia and the microenvironments of solid tumors are often accompanied by extracellular pH (acidosis) reductions that may result in inhibited immune function[3], enhanced normal cell necroptosis[4], and increased tumor invasion[5]. GPR68 is usually coupled with Gq/11 and activates phospholipase C (PLC)/Ca2+ signaling, and GPR4, GPR65 and GPR132 typically activate the adenylyl cyclase/cAMP/PKA pathway through Gs proteins[14,16]. We found that the osteogenic activities of BMSCs were decreased with reductions in the extracellular pH and that GPR4-induced suppression of YAP might be an important mechanism by which proton-induced anti-osteogenic effects are elicited in BMSCs because these effects could be blocked by the inhibition of GPR4 or the activation of YAP. To the best of our knowledge, this study is the first to demonstrate the inhibitory effects of protons on the osteogenesis of BMSCs and elucidate the underlying mechanism
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