Resolving the Two "Bony" Faces of PPAR-gamma

Abstract

Bone loss with aging results from attenuated and unbalanced bone turnover that has been associated with a decreased number of bone forming osteoblasts, an increased number of bone resorbing osteoclasts, and an increased number of adipocytes (fat cells) in the bone marrow. Osteoblasts and adipocytes are derived from marrow mesenchymal stroma/stem cells (MSC). The milieu of intracellular and extracellular signals that controls MSC lineage allocation is diverse. The adipocyte-specific transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) acts as a critical positive regulator of marrow adipocyte formation and as a negative regulator of osteoblast development. In vivo, increased PPAR-gamma activity leads to bone loss, similar to the bone loss observed with aging, whereas decreased PPAR-gamma activity results in increased bone mass. Emerging evidence suggests that the pro-adipocytic and the anti-osteoblastic properties of PPAR-gamma are ligand-selective, suggesting the existence of multiple mechanisms by which PPAR-gamma controls bone mass and fat mass in bone.

Figure 1

Schematic representation of bone cell development.

Figure 2

The effect of tested glitazones on adipocyte (a) and osteoblast (b) phenotypes of U-33/γ2 cells. U-33/γ2 cells represent marrow mesenchymal bipotential progenitor cells, which differentiation towards osteoblast and adipocyte is under the control of PPAR-γ2 transcription factor. Cells were treated for 3 days with different doses of tested PPAR-γ agonists and cultures were either stained for fat with Oil Red-O or subjected to alkaline phosphatase enzyme activity assay as previously described [4].