A research group from the Florida campus of The Scripps Research Institute (TSRI) has identified a new therapeutic approach that could promote the development of new bone-forming cells in patients suffering from bone loss.
The study was published in the journal Nature Communications, and it focused on a protein called PPARγ, which is a master regulator of fat, and the impact of this molecule on the fate of mesenchymal stem cells derived from bone marrow. Since these mesenchymal stem cells can differentiate into several different cell types, including fat, connective tissues, bone and cartilage. Consequently mesenchymal stem cells have a number of potentially important therapeutic applications.
A partial loss of PPARγ in a genetically modified mouse model led to increased bone formation. Could the use of drugs to inhibit PPARγ and potentially mimic that effect? This group combined a variety of structural biology approaches and then tried to design drugs that could fit PPARγ. This type of strategy is called “rational design,” and this yielded a new compound that could repress the biological activity of PPARγ.
The new drug, SR2595 (SR=Scripps Research), when applied to mesenchymal stem cells, significantly increased bone cell or osteoblast formation, a cell type known to form bone.
“These findings demonstrate for the first time a new therapeutic application for drugs targeting PPARy, which has been the focus of efforts to develop insulin sensitizers to treat type 2 diabetes,” said Patrick Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida. “We have already demonstrated SR2595 has suitable properties for testing in mice; the next step is to perform an in-depth analysis of the drug’s efficacy in animal models of bone loss, aging, obesity and diabetes.”
In addition to identifying a new, potential therapeutic use for bone loss, this study may have even broader implications.
“Because PPARG is so closely related to several proteins with known roles in disease, we can potentially apply these structural insights to design new compounds for a variety of therapeutic applications,” said David P. Marciano, first author of the study, a recent graduate of TSRI’s PhD program and former member of the Griffin lab. “In addition, we now better understand how natural molecules in our bodies regulate metabolic and bone homeostasis, and how unwanted changes can underlie the pathogenesis of a disease.” Marciano will focus on this subject in his postdoctoral work in the Department of Genetics at Stanford University.