Abstract
Monocarboxylate transporter-1 (MCT-1) is a transmembrane transporter for monocarboxylates including lactate and pyruvate. Silencing Mct1 by its small interfering RNA (siRNA) suppressed the expression of marker genes for osteoblast differentiation, namely, Tnap, Runx2, and Sp7, induced by BMP-2 in mouse myoblastic C2C12 cells. Mct1 siRNA also suppressed alkaline phosphatase activity, as well as expressions of Tnap and Bglap mRNAs in mouse primary osteoblasts. On the other hand, Mct1 siRNA did not have effects on the Smad1/5 or ERK/JNK pathways in BMP-2-stimulated C2C12 cells, while it up-regulated the mRNA expression of p53 (Trp53) as well as nuclear accumulation of p53 in C2C12 cells in a BMP-2-independent manner. Suppression of osteoblastic differentiation by Mct1 siRNA in C2C12 cells was abolished by co-transfection of Trp53 siRNA. Together, these results suggest that MCT-1 functions as a positive regulator of osteoblast differentiation via suppression of p53.
Highlights
Monocarboxylate transporters (MCTs) are a group of transmembrane transporters for monocarboxylates
We found that an Monocarboxylate transporter-1 (MCT-1)-dependent increase in mitochondrial reactive oxygen species (ROS) production was required for late phase activation of NF-κB, which led to expression of NOX-2 in ATDC5 cells stimulated by IL-1β
Since intracellular lactate is thought to be generated as a result of glycolysis, its elevated concentration is assumed to be the result of suppressed efflux of lactate through MCT-1 in Mct[1] small interfering RNA (siRNA)-introduced C2C12 cells
Summary
Monocarboxylate transporters (MCTs) are a group of transmembrane transporters for monocarboxylates. We found that an MCT-1-dependent increase in mitochondrial ROS production was required for late phase activation of NF-κB, which led to expression of NOX-2 in ATDC5 cells stimulated by IL-1β Together, those observations suggested that MCT-1 might have possible hidden functions, in addition to regulation of energy metabolism and intracellular pH. We have shown that acetoacetate enhanced and β-hydroxybutyrate suppressed mineralization by mouse osteoblastic MC3T3-E1 cells, in both the presence and absence of bone morphogenetic protein (BMP)-26. These ketone bodies are known to be transported across plasma membranes via MCT-11, while knockdown of Mct[1] nullified their effects[6]. We examined the role of MCT-1 in activation of p53, a negative regulator of osteoblast differentiation[9]
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