PURPOSE: Osteosarcoma is the most common primary malignancy of bone. The long-term
survival of osteosarcoma patients hinges on our ability to prevent and/or treat recurrent and
metastatic lesions. Here, we investigated the activation of peroxisome proliferator-activated
receptor gamma (PPARgamma) and retinoid receptors as a means of differentiation therapy for
human osteosarcoma.
EXPERIMENTAL DESIGN: We examined the endogenous expression of PPARgamma and
retinoid receptors in a panel of osteosarcoma cells. Ligands or adenovirus-mediated overexpression
of these receptors were tested to inhibit proliferation and induce apoptosis of osteosarcoma cells.
Osteosarcoma cells overexpressing the receptors were introduced into an orthotopic tumor model.
The effect of these ligands on osteoblastic differentiation was further investigated.
RESULTS: Endogenous expression of PPARgamma and isotypes of retinoic acid receptor (RAR)
and retinoid X receptor (RXR) is detected in most osteosarcoma cells. Troglitazone, 9-cis retinoic
acid (RA), and all-trans RA, as well as overexpression of PPARgamma, RARalpha, and RXRalpha,
inhibit osteosarcoma cell proliferation and induce apoptosis. A synergistic inhibitory effect on
osteosarcoma cell proliferation is observed between troglitazone and retinoids, as well as with the
overexpression pairs of PPARgamma/RARalpha, or PPARgamma/RXRalpha. Overexpression of
PPARgamma, RARalpha, RXRalpha, or in combinations inhibits osteosarcoma tumor growth and
cell proliferation in vivo. Retinoids (and to a lesser extent, troglitazone) are shown to promote
osteogenic differentiation of osteosarcoma cells and mesenchymal stem cells.
CONCLUSIONS: Activation of PPARgamma, RARalpha, and RXRalpha may act synergistically
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on inhibiting osteosarcoma cell proliferation and tumor growth, which is at least partially mediated
by promoting osteoblastic differentiation of osteosarcoma cells.