Mechanical Stretching and Signaling Pathways in Adipogenesis - The Mechanobiology of Obesity and Related Diseases - page 42

3.4 Rho-Rho-Kinase Pathway
It has been well-established that the small GTPase Rho family proteins regulate
many cellular processes, including cytoskeletal rearrangement, cell motility, and
cell shape [ 57 , 70 - 73 ]. A growing body of evidence suggests that the Rho family
proteins are actually involved in the mechanotransduction (Fig. 3 ) especially in the
cells belonging to the mesodermal origin [ 74 , 75 ]. McBeath and colleagues have
demonstrated that a molecular basis for the cell-shape-controlled lineage com-
mitment of MSCs [ 76 ], in which there was a blockade of endogenous RhoA
activity by expressing its dominant negative form, committed MSCs to differen-
tiate into adipocyte direction, while constitutive activation of RhoA induced
osteogenesis. This finding would provide an important insight about the roles of
biomechanical stresses, which are ontogenically generated both internally and
externally in our body, on the different possible stem cell fates, such as osteo-
genesis, adipogenesis, and myogenesis.
On the other hand, Hara and colleagues have demonstrated that the static
stretch-induced and obesity-induced (where static stretch of intrinsic adipocyte
should occur during progression of obesity) Rho and Rho-kinase activity in mature
hypertrophic adipocytes contribute to phenotypical and functional changes,
showing upregulation of macrophage chemoattractant protein-1 (MCP-1) and
downregulation of adiponectin expressions, as a vicious cycle mechanism in the
obese adipose tissues [ 35 ].
These results imply that the mechanically induced Rho-Rho-kinase signaling
plays differential roles in developmental and/or metabolic aspects of adipocytes,
i.e., before and after the commitment as well as post-maturation stage with or
without hypertrophy, possibly depending on their different physiological, patho-
logical, and environmental conditions [ 35 ].
3.5 Dual Effects of ERK in the Stretch-Induced Response
on Adipogenesis
Various mitogenic stimuli activate the ERK/MAPK signaling [ 77 ]. Actually, ERK/
MAPK are involved in a variety of cellular events, including cell adhesion, cell
survival, cell migration, cell cycle progression and proliferation, cell differentia-
tion, transcription, and metabolism [ 78 ]. It is widely recognized that ERK/MAPK
plays a pivotal role in the mechanotransduction pathway in a variety of cell types,
such as cardiomyocytes [ 79 ], vascular endothelial cells [ 80 ], and vascular smooth
muscle cells [ 81 ], glomerular mesangial cells [ 82 ], osteoblasts [ 83 ], fibroblasts
[ 84 ], preadipocytes and/or differentiating-adipocytes [ 14 ], different MSCs
including dental pulp stem cells [ 85 ], C3H10T1/2 cells [ 30 ], ASCs, and embryonic
stem cells (ESCs) [ 86 ].