Table 1.

Role of Reactive Oxygen Species in Osteogenic and Adipogenic Differentiation

Source	Osteogenic differentiation	Adipogenic differentiation
Intracellular
Mitochondria	mtDNA copy number, protein subunits of respiratory enzymes and oxygen consumption rate are upregulated while intracellular H2O2 and O2•− are reduced after osteogenic induction [51]	Inhibition of the mitochondrial electron transport chain suppresses MSC adipogenic differentiation [76]
	Oxidative stress in aged mice results in reduced osteoblast and bone formation, increased osteoblast and osteocyte apoptosis and decreased bone density [84]	ROS produced by mitochondrial complex III are required for activation of adipogenesis. Intracellular ROS increase after exposure of MSCs to an adipogenic cocktail [139]
		NOX4 mRNA expression is decreased while NOX2 mRNA expression is unchanged during adipogenic differentiation [92]
NAPDH oxidase	NOX4 knockout mice display higher bone density. NOX4 is involved in the transformation of osteoblasts to osteoclasts and is thus responsible for reduced bone density [112]	NOX4 increases lipid accumulation even in the absence of insulin. siRNA against NOX4 inhibit insulin-induced accumulation of lipid droplets in 3T3-L1 cells. Overexpression of NOX4 increases adipogenesis [22]
		Elevated oxidative stress and consequently elevated NADPH oxidase in accumulated fat is related to obesity-associated metabolic syndrome in humans and mice [85]
		NOX4 induces adipogenesis in adipose-derived MSCs [87]
		Knock down of NOX4 inhibits MSC adipogenic differentiation even in the presence of an adipogenic cocktail [92]
		Reduced expression of NOX4 is a hallmark of adipogenesis in 3T3-L1 cells [85,92,141]
Extracellular	H2O2 reduces Alp activity in osteogenic induced hMSC [51]	H2O2 induced oxidative stress induces MSC adipogenesis [22]
	H2O2 abolishes osteogenesis in osteoblast progenitors [84]	Treating 3T3-L1 cells with H2O2 results in adipogenesis even in the absence of insulin [85]
	H2O2 induced oxidative stress reduces Gli protein levels thus preventing Hh signaling and reducing osteogenesis. The level of Alp mRNA expression is reduced [111]	H2O2 increase adipogenesis in 3T3-L1 cells in a dose-dependent manner [86]
	H2O2 inhibits expression of osteogenic differentiation markers in MC3T3-E1 and M2-10B4 cell lines. Alp activity is also reduced [79]	H2O2 diminishes expression of adipo-cytokines [87]
		eNOS rather than iNOS governs adipogenesis. NO stimulates rat preadipocyte differentiation [93]

eNOS, endothelial nitric oxide synthases; iNOS, inducible nitric oxide synthases; MSC, mesenchymal stromal cell; ROS, reactive oxygen species.