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J Biol Chem, Vol. 275, Issue 19, 14388-14393, May 12, 2000
From The nuclear receptor and transcription factor,
peroxisome proliferator-activated receptor-
Activation of Peroxisome Proliferator-activated Receptor-
Pathway Inhibits Osteoclast Differentiation*
§,,,,,, and
Osiris Therapeutics, Inc., Baltimore, Maryland
21231, the ¶ Barnes-Jewish Hospital at Washington University
School of Medicine, St. Louis, Missouri 63110, and The Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205
(PPAR-), regulates
the activity of other transcription factors in the adipogenic
differentiation and inflammatory response pathways. We examined the
possible function of the PPAR- pathway in osteoclast (Ocl) formation
from CD34+ hematopoietic stem cells
(CD34+ HSCs), using a co-culture system comprised of human
mesenchymal stem cells (hMSCs) 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-colony stimulating
factor (M-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 M-CSF.
CD34+ HSCs, but not hMSCs, express PPAR-, and
15-deoxy-
12,14-prostaglandin-J2 (15d-PG-J2), a PPAR-
agonist, completely blocked the effects of sOPGL and M-CSF on Ocl
formation and activity. The inhibitory effect of 15d-PG-J2 is specific
to the Ocl lineage in both human and mouse models of
osteoclastogenesis. Accordingly, parallel experiments demonstrate that
sOPGL activates the NF-
B pathway within mouse Ocl progenitors, and
this effect was abolished by 15d-PG-J2. These data establish a link
between PPAR- and OPGL signaling within Ocl progenitors, and support
a role for PPAR- pathway in the modulation of osteoclastogenesis.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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