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 PPARγ full agonists, they can activate PPARγ in a ligand-dependent way. Recent studies indicate that these PPARγ full agonists have some side effects, such as weight gain and bone loss, which may increase the risk of osteoporosis. In contrast, selective PPARγ Modulators (SPPARγMs) are novel PPARγ ligands that can activate PPARγ 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, PPARγ 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 SPPARγMs was much less than that displayed by rosiglitazone. We found that the enhancement of PPARγ 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 PPARγ ligands, especially rosiglitazone. In conclusion, reduced osteoclasts differentiation characteristic of SPPARγMs highlights SPPARγMs potential as therapeutic targets in diabetes, versus traditional antidiabetic drugs.

Thiazolidinediones (TZD) are widely prescribed for the treatment of Type 2 diabetes. Increased loss of bone mass and a higher incidence of fractures have been associated with the use of this class of drugs in post-menopausal women. In vitro studies performed in rodent cell models indicated that rosiglitazone (RGZ), one of the TZD, inhibited osteoblastogenesis and induced adipogenesis in bone marrow progenitor cells. The objective of the present study was to determine for the first time the RGZ-dependent shift from osteoblastogenesis toward adipogenesis using a human cell model. To this purpose, bone marrow-derived mesenchymal stem cells were characterized and induced to differentiate along osteogenic and adipogenic lineages. We found that the exposure to RGZ potentiated adipogenic differentiation and shifted the differentiation toward an osteogenic phenotype into an adipogenic phenotype, as assessed by the appearance of lipid droplets. Accordingly, RGZ markedly increased the expression of the typical marker of adipogenesis fatty-acid binding protein 4, whereas it reduced the expression of Runx2, a marker of osteoblastogenesis. This is the first demonstration that RGZ counteracts osteoblastogenesis and induces a preferential differentiation into adipocytes in human mesenchymal stem cells.

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in insulin sensitivity, tissue homeostasis, and regulating cellular functions. We found high-level expression of PPARgamma in embryo mouse brain and neural stem cells (NSCs), in contrast to extremely low levels in adult mouse brain. Here, we show that PPARgamma mediates the proliferation and differentiation of murine NSCs via up-regulation of the epidermal growth factor receptor and activation of the ERK pathway. Cell growth rates of NSCs prepared from heterozygous PPARgamma-deficient mouse brains, PPARgamma-RNA-silenced NSCs, and PPARgamma dominant-negative NSCs were significantly decreased compared with those of wild-type NSCs. Physiological concentrations of PPARgamma agonists, rosiglitazone and pioglitazone, stimulated NSC growth, whereas antagonists caused cell death in a concentration-dependent manner via activation of the caspase cascade. The stimulation of cell growth by PPARgamma was associated with a rapid activation of the ERK pathway by phosphorylation and up-regulation of epidermal growth factor receptor and cyclin B protein levels. In contrast, activation of PPARgamma by agonists inhibited the differentiation of NSCs into neurons. The inhibition of differentiation was associated with an activation of STAT3. These data indicate that PPARgamma regulates the development of the central nervous system during early embryogenesis via control of NSC proliferation.