Table 2.

Environmental stress, hormone drugs and biological/pathological factors regulate BMSCs differentiation via altering energy metabolism.

Other factors	Fuctions	Metabolic mechanism	References
Environmental stress
ECM stiffness	High ECM stiffness promotes osteogenic differentiation of hMSCs and BMSCs	Enhances ATP levels and AMPK activation; promotes mitochondriogenesis and declines mitochondria fission	[[57], [58], [59]]
Hypoxia	Suppresses adipogenesis and enhances osteogenesis of hMSCs	Promotes pyruvate dehydrogenase (PDH) by PDH kinase (PDK) and inhibits glycolytic enzymes	[63]
	Inhibits both osteogenic and adipogenic differentiation of MSCs	Inhibits oxidative and enhances glycolysis	[[64], [65], [66]]
Microgravity	Suppresses osteogenic differentiation of MSCs; promotes adipogenic differentiation of BMSCs	Inhibits OXPHOS and decreases the expression of important energy sensor Sirt1; upregulates leptin expression	[73,74]
Hormone drugs
PTH	Inhibits adipogenesis in murine cell lines of adipocyte progenitors BMSCsadipo, enhances osteogenesis of BMSCs	Impaires insulin signaling, enhances glycolysis and ATP production rate; promotes BMAT lipolysis and provides more fatty acids to fuel osteogenic differentiation	[76,77]
Dexamethasone	Inhibits osteogenic differentiation of BMSCs	Impaires mitochondrial function and downregulates mitochondrial metabolism AMPK/PGC-1 α/Sirt3 axis to induce ROS overproduction	[79,80]
Biological factors
MicroRNAs	MiR-34a overexpression impaires osteogenic differentiation of hMSCs; miR-181a/b can promote osteogenesis;	Inhibits lactate dehydrogenase-A (LDHA), hexokinase 2 (HK2), and Glut1-mediated glycolysis; enhances mitochondrial metabolism	[26,86,87]
	MicroRNA-200a-3p suppresses osteogenic differentiation of MSCs	Inhibits GLS	[88]
Adiponectin	Promotes osteoblastogenesis in C3H10T1/2 cells	Induces ALP, osteopontin expression	[92,96,97]
	Inhibits the adipogenic commitment of BMSCs	Increases AdipoR1, KDM6B and KDM4B to inhibit PPARγ	[92,98,99]
Agin	Inhibits osteogenic differentiation and promtes adipogenic differentiation of BMSCs	Downregulates mitochondria metabolism related NAD+, PGC-1α levels as well as citrate contents in bone matrix	[[101], [102], [103], [104], [105]]
Pathological factors
Obesity/diabetes mellitus	Inhibits osteogenic differentiation and promotes adipogenic differentiation of BMSCs	Increases DPP4 to inhibiting glucose metabolism and lipolysis	[[110], [111], [112]]
Osteoporosis	Impaires osteogenic differentiation of MSCs, SSCs and BMSCs	Inhibits fatty acid synthase expression; decreases mitochondrial biogenesis, PGC1α level and Sirt 3 expression	[104,[114], [115], [116], [117]]
Anorexia nervosa	Increases adipogenic differentiation of BMSCs while blunts osteogenic differentiation	Downregulates Sirt1 expression; blocks BMPs signaling and activates the inflammatory NF-κB signaling via adipokines derived from bone marrow adipose in pathological state	[[121], [122], [123]]