Regulation of Selective PPARγ Modulators in the Differentiation of Osteoclasts

Diabetes is the most common chronic disease in the world and causes complications with many diseases, such as heart disease and osteoporosis. Osteoporosis is a systemic bone disease characterized by imbalance in bone resorption and bone formation. Osteoclast is type of bone cell that functions in bone resorption and plays a critical role in bone remodeling. Rosiglitazone and pioglitazone, which belong to Thiazolidinediones(TZDs), are commonly used antidiabetic drugs. As PPAR full agonists, they can activate PPAR in a ligand-dependent way. Recent studies indicate that these PPAR full agonists have some side effects, such as weight gain and bone loss, which may increase the risk of osteoporosis. In contrast, selective PPAR Modulators (SPPARMs) are novel PPAR ligands that can activate PPAR in different ways and lead to distinct downstream genes. Mice bone marrow cells were stimulated with recombinant mouse RANKL and M-CSF to generate osteoclasts. To determine the effect on osteoclasts formation, PPAR ligands (Rosiglitazone, Fmoc-L-Leu, and Telmisartan) were added at the beginning of the culture. Rosiglitazone significantly increased the differentiation of multinucleated osteoclasts, while osteoclasts formation triggered by SPPARMs was much less than that displayed by rosiglitazone. We found that the enhancement of PPAR ligands may be associated with TRAF6 and downstream ERK signal pathway. We also demonstrated osteoclasts show characteristic M2 phenotype and can be further promoted by PPAR ligands, especially rosiglitazone. In conclusion, reduced osteoclasts differentiation characteristic of SPPARMs highlights SPPARMs potential as therapeutic targets in diabetes, versus traditional antidiabetic drugs. J. Cell. Biochem. 114: 1969-1977, 2013. (c) 2013 Wiley Periodicals, Inc.