Activation of mitochondria is an acute Akt-dependent response during osteogenic differentiation
bioRxiv (Cold Spring Harbor Laboratory)(2020)
Abstract
Osteogenic differentiation, the process by which bone marrow mesenchymal stem/stromal (a.k.a. skeletal stem) cells and osteoprogenitors form osteoblasts, is a critical event for bone formation during development, fracture repair, and tissue maintenance. Extra- and intracellular signaling pathways triggering osteogenic differentiation are relatively well known; however, the ensuing change in cell energy metabolism is less clearly defined. Here we tested the effect of osteogenic media containing ascorbate and β-glycerol phosphate, or various osteogenic hormones and growth factors on energy metabolism in long bone (ST2)- and calvarial bone (MC3T3-E1)-derived osteoprogenitors. We show that osteogenic media, and differentiation factors, Wnt3a and BMP2, stimulate mitochondrial oxidative phosphorylation (OxPhos) with little effect on glycolysis. The activation of OxPhos occurs acutely, suggesting a metabolic signaling change rather than protein expression change. To this end, we found that the observed mitochondrial activation is Akt-dependent. Akt is activated by osteogenic media, Wnt3a, and BMP2, leading to increased phosphorylation of various mitochondrial Akt targets, a phenomenon known to stimulate OxPhos. In sum, our data provide comprehensive analysis of cellular bioenergetics during osteoinduction in cells of two different origins (mesenchyme vs neural crest) and identify Wnt3a and BMP2 as physiological stimulators of mitochondrial respiration via Akt activation.
* AA
: Antimycin A
ALP
: Alkaline phosphatase
BMP2
: Bone Morphogenic Protein 2
CV
: Crystal Violate
ECAR
: Extracellular Acidification Rate
FCCP
: Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone
OBM
: Osteoblastic media a.k.a. Ascorbic acid and beta-gycero phosphate
OBs
: Osteoblasts
OCR
: Oxygen Consumption Rate
Oligo
: Oligomycin
OxPhos
: Oxidative Phosphorylation
ROS
: Reactive Oxygen Species
ROT
: Rotenone
Wnt3a
: Wingless protein 3a
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