UCSF

The unique material properties of skeletal matrices are critical for musculoskeletal tissue function. For example, bone matrix material properties (BMMPs) - including elastic modulus, hardness, and fracture toughness - reflect the ability of bone matrix to resist deformation and catastrophic failure. However, the mechanisms by which these properties are established remain unclear. Many reports support a role for TGF-&beta and Smad3 in regulating the skeletal matrix. Thus, we hypothesized that Smad3 is essential for maintaining the extracellular matrix in bone, cartilage, and tendon.

Previously, our lab determined that TGF-&beta regulates BMMPs in development by signaling through its intracellular effector, Smad3. Here, we showed that BMMPs could also be regulated by pharmacologically disrupting TGF-&beta signaling. To further dissect the mechanism of BMMP regulation, we identified the downstream targets of TGF-&beta signaling. In vitro studies showed that TGF-&beta inhibits osteoblast differentiation by Smad3 repression of Runx2 function. Using nanoindentation, we found that TGF-&beta regulation of BMMPs through Smad3 is also Runx2-dependent. We further show that osteopontin, a matrix protein regulated by both TGF-&beta and Runx2, is essential for normal bone matrix material properties.

Our results establish a mechanism through which TGF-&beta regulates BMMPs to maintain healthy bone. This suggests a paradigm in which matrix material properties are established by growth factors through their regulation of lineage-specific transcription factors. Indeed, our further studies in cartilage and tendon indicate an essential role for TGF-&beta/Smad3 signaling in regulating cell lineage-specific transcription factor expression and activity as well as matrix structure and composition. We anticipate that our research will lead to the identification of novel diagnostic strategies and therapeutics for the prevention or treatment of skeletal diseases, as well as aid in the development of improved biomaterials for tissue regeneration.