Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors that play a role in regulating cell differentiation, development, and lipid metabolism. The PPARs are categorized into three subtypes, PPARα, PPARγ, and PPARδ (or –β) and numerous selective synthetic ligands, including marketed drugs, are available for the PPARα and PPARγ isoforms. PPARδ remains the only PPAR subunit where there is no available marketed drug. Also, there are only a few known investigational selective and potent PPARδ agonists, with GW0742 and GW501516 being the most studied. Previously, we have shown that a PPARδ agonist can control mesenchymal stem cell (MSC) differentiation by promoting osteogenesis. Others have confirmed this observation and reported that this differentiation occurs by PPARδ direction of the Wnt pathway.<sup> </sup>In lipid metabolism, PPARγ and PPARδ function in similar but opposite ways,<sup> </sup>and we have shown that this opposing action can be extended to contrasting control of MSC differentiation. Treatment of bone marrow-derived MSCs with the PPARγ agonist, rosiglitazone, results in adipogenesis whereas treatment with the PPARδ agonist, GW0742, results in osteogenesis. We have synthesized a library of novel, small molecule PPAR ligands for further exploring the structure-activity relationship (SAR) of the PPARδ subunit and the role it plays in MSC osteogenesis. Our results show that our library contains compounds with various MSC differentiation phenotypes, with several giving an osteogenic response comparable to that of GW0742. These select compounds have been further tested in an ovariectomy (OVX) induced mouse model of postmenopausal osteoporosis. Our compounds showed the ability to increase tibial bone density and trabecular thickness with the overall results suggesting PPARδ agonists as a possible novel treatment option for osteoporosis and other bone-related diseases.

Synthesis of PPAR ligands for the control of mesenchymal stem cell differentiation: Novel treatment avenue for osteoporosis

2019 Fall National Meeting

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