A new therapeutic approach, although still preliminary, could encourage the growth of new bone-forming cells in patients suffering from bone loss.
Scientists at the Scripps Research Institute have identified a protein, known as the master regulator of fat, called PPARy for its impact on the fate of stem cells derived from bone marrow, known as mesenchymal stem cells.
Mesenchymal stem cells are able to develop into several different cell types, including fat, connective tissues, bone and cartilage, so they have a number of potentially important therapeutic applications.
It was previously established that a limited loss of PPARy in a genetically modified mouse model led to increased bone formation. To discover whether they could mimic that effect using a drug candidate, the researchers used a number of structural biology approaches in combination to rationally design a new compound that could repress the biological activity of PPARy.
They found that when human mesenchymal stem cells were treated with the new compound, which they called SR2595 (SR=Scripps Research), there was a statistically significant increase in osteoblast formation, a cell type known to form bone.
Patrick Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, said:
“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. 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.”
Above and beyond finding a potential new therapeutic for bone loss, the study could have broader implications, said first author David P. Marciano:
“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. 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.”
David P. Marciano, Dana S. Kuruvilla, Siddaraju V. Boregowda, Alice Asteian, Travis S. Hughes, Ruben Garcia-Ordonez, Cesar A. Corzo, Tanya M. Khan, Scott J. Novick, HaJeung Park, Douglas J. Kojetin, Donald G. Phinney, John B. Bruning, Theodore M. Kamenecka & Patrick R. Griffin
Pharmacological repression of PPARγ promotes osteogenesis
Nature Communications 6, 7443 doi:10.1038/ncomms8443
“The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulator of adipogenesis and the pharmacological target of the thiazolidinedione (TZD) class of insulin sensitizers. Activation of PPARγ by TZDs promotes adipogenesis at the expense of osteoblast formation, contributing to their associated adverse effects on bone. Recently, we reported the development of PPARγ antagonist SR1664, designed to block the obesity-induced phosphorylation of serine 273 (S273) in the absence of classical agonism, to derive insulin-sensitizing efficacy with improved therapeutic index.
Here we identify the structural mechanism by which SR1664 actively antagonizes PPARγ, and extend these findings to develop the inverse agonist SR2595. Treatment of isolated bone marrow-derived mesenchymal stem cells with SR2595 promotes induction of osteogenic differentiation. Together these results identify the structural determinants of ligand-mediated PPARγ repression, and suggest a therapeutic approach to promote bone formation.”
Photo: A confocal microscope image of a small segment of bone from the vertebra of an elderly woman who suffered from osteoporosis. Credit Professor Alan Boyde, Wellcome Images, Creative Commons by-nc-nd 4.0