- Mesenchymal stem cell differentiation: Osteoblast/Adipocyte
- Mechanical control of bone remodeling
- Mechanical control of cytoskeletal remodeling
The skeleton is a complex tissue that is able to regulate its own mass and architecture to meet two critical and competing responsibilities: one structural and the other metabolic. The structure of bone is determined largely through its ability to respond to daily loading with intelligent remodeling. When mechanical signals are suppressed (no exercise, space travel, getting old) bone structure degenerates – and bone resorption outpaces bone formation. If skeletal degeneration is severe it will lead to catastrophic failure with fracture. Alternatively, daily skeletal loading leads to bone formation, enhancing not only the activity of bone osteoblasts to make new bone, but also promotes the entry of mesenchymal stem cells into the osteogenic lineage. Our cellular and molecular biological investigations are aimed at understanding mechanical and hormonal control of bone remodeling.
A primary focus is to understand the mechanosensory apparatus of the mesenchymal stem cell. Mechanical force alters the cytoskeleton, which repositions signaling molecules both at the plasma membrane and at the nuclear envelope. We found that focal adhesion assembly augments mechanical signal transduction, and mTORC2 activation of Akt not only stimulates beta-catenin signaling, but also RhoA stimulated cytoskeletal rearrangement. Recently we found that LINC proteins connecting the cytoplasmic cytoskeleton to the nucleus are critical for transmitting mechanical force, both for high magnitude strain events, and for high frequency, low strain events. We are considering how this might alter signal transduction events at the nuclear envelope, including inward nuclear transport of beta-catenin.
A secondary focus in the laboratory is on intranuclear actin. We have found that intranuclear actin can strongly promotes osteoblastic differentiation of MSCs, and that this is replayed in the live mouse tibiae. We are considering how actin rearrangement within the nucleus thus affects gene expression.
We also utilize a live mouse running model to understand how exercise promotes osteoblastic bone formation. We have shown that running decreases fat storage, and potentially adipocyte differentiation, in control, high fat fed, and in obese mice.