IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1

IL-4 is a pleiotropic immune cytokine secreted by activated T(H)2 cells tha t inhibits bone resorption both in vitro and in vivo. The cellular targets of IL-4 action as well as its intracellular mechanism of action remain to b e determined. We show here that IL-4 inhibits receptor activator of NF-kapp aB ligand-induced osteoclast differentiation through an action on osteoclas t precursors that is independent of stromal cells. Interestingly, this inhi bitory effect can be mimicked by both natural as well as synthetic peroxiso me proliferator-activated receptor gamma1 (PPAR gamma1) ligands and can be blocked by the irreversible PPAR gamma antagonist GW 9662. These findings s uggest that the actions of IL-4 on osteoclast differentiation are mediated by PPAR gamma1, an interpretation strengthened by the observation that IL-4 can activate a PPAR gamma1-sensitive luciferase reporter gene in RAW264.7 cells. We also show that inhibitors of enzymes such as 12/15-lipoxygenase a nd the cyclooxygenases that produce known PPAR gamma1 ligands do not abroga te the IL-4 effect. These findings, together with the observation that bone marrow cells from 12/ 15-lipoxygenase-deficient mice retain sensitivity to IL-4, suggest that the cytokine may induce novel PPAR gamma1 ligands. Our results reveal that PPAR gamma1 plays an important role in the suppression of osteoclast formation by IL-4 and may explain the beneficial effects of t he thiazolidinedione class of PPAR gamma1 ligands on bone loss in diabetic patients.