New insights into peroxisome proliferatoractivated receptor gamma action: Stimulation of human osteoblast differentiation

Peroxisome proliferator-activated receptor γ (PPARG) is a member of the nuclear receptor superfamily, which orchestrates responses to environmental factors by sensing diverse nutrients and xenobiotics. Imbalances in nuclear receptor signalling have been associated with various aging-related diseases, e.g. osteoporosis, metabolic syndromes and cancer. Two PPARG proteins exist derived from one single gene by alternative promoter usage and splicing: PPARγ1, which is translated from three alternative transcripts PPARG1, 3 and 4, and PPARγ2, which is translated from PPARG2 transcript. PPARG2 is known to control adipogenesis. Here we report our recent findings concerning the presence, regulation and functional significance of PPARG signalling during differentiation and mineralization of our human osteoblast cell model SV-HFO.
The latter can be induced by dexamethasone (dex) to differentiate and to mineralize the extracellular matrix formed in a three-week period. Realtime-PCR analysis of the four PPARG transcripts revealed a at least 250, 30 and 150-fold higher expression of PPARG1, 3 and 4, respectively, compared to PPARG2 at all time points during culture. This markedly contrasts the expression pattern in adipocytes in which PPARG2 is strongly expressed. Expression of the four
PPARG transcripts increased during differentiation, with PPARG3 showing strongest induction. Short-term dex-treatment for three hours increased expression of all four PPARG transcripts suggesting direct regulation by dex.
We furthermore studied the effect of PPARG ligands on human osteoblast differentiation and mineralization. Treatment with rosiglitazone, a PPARG-specific agonist, resulted in significant increases in alkaline phosphatase (ALP) activity and mineralization at all three time points during culture. The PPARG antagonist GW9662, however, revealed a significant decrease in ALP activity and did not show any effect on mineralization. In conclusion, PPARG expression is controlled by cell-type specific promoter usage and splicing, leading to PPARG1, 3 and 4 (= PPARγ1) expression in osteoblasts and PPARG2 (= PPARγ2) expression in adipocytes. The PPARG ligand rosiglitazone does not exclusively control adipocyte differentiation but also stimulates human osteoblast differentiation. Our data implicate an alternative view on PPARG in the balance between adipocyte and osteoblast differentiation in relation to the development of osteoporosis.