Activation of peroxisome proliferator-activated receptor-gamma pathway inhibits osteoclast differentiation

The nuclear receptor and transcription factor, peroxisome proliferator-acti vated receptor-gamma (PPAR-gamma), regulates the activity of other transcri ption factors in the adipogenic differentiation and inflammatory response p athways. We examined the possible function of the PPAR-gamma pathway in ost eoclast (Ocl) formation from CD34(+) hematopoietic stem cells (CD34(+) HSCs ), using a co-culture system comprised of human mesenchymal stem cells (hMS Cs) and CD34(+) HSCs, both derived from bone marrow. Ocl formation in this co-culture system is enhanced by the addition of exogenous osteoprotegerin ligand (OPGL), an essential Ocl differentiation factor, and macrophage-colo ny stimulating factor (IM-CSF). The data indicate that soluble OPGL (sOPGL) and M-CSF stimulate Ocl formation in the co-cultures up to 4-fold compared with CD34(+) HSCs alone treated with sOPGL and IM-CSF. CD34(+) HSCs, but n ot hMSCs, express PPAR-gamma, and 15-deoxy-Delta(12,14)-prostaglandin-J2 (1 5d-PG-J2), a PPAR-gamma agonist, completely blocked the effects of sOPGL an d M-CSF on Ocl formation and activity. The inhibitory effect of 15d-PG-J2 i s specific to the Ocl lineage in both human and mouse models of osteoclasto genesis. Accordingly, parallel experiments demonstrate that sOPGL activates the NF-kappa B pathway within mouse Ocl progenitors, and this effect was a bolished by 15d-PG-J2. These data establish a link between PPAR gamma and O PGL signaling within Ocl progenitors, and support a role for PPAR-gamma pat hway in the modulation of osteoclastogenesis.