G. Mbalaviele et al., Activation of peroxisome proliferator-activated receptor-gamma pathway inhibits osteoclast differentiation, J BIOL CHEM, 275(19), 2000, pp. 14388-14393
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.