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From the Departments of Pharmacology/Pathology,*
Cell
Biology,
Protein
Chemistry,
Mammalian Cell Molecular
Biology,§
and Mammalian
Genomics,¶
Amgen, Inc., Thousand Oaks, California
Osteoprotegerin ligand (OPGL) targets osteoclast precursors and
osteoclasts to enhance differentiation and activation,
however, little is known about OPGL effects on osteoclast
survival. In vitro, the combination of OPGL +
colony-stimulating factor-1 (CSF-1) is required for optimal
osteoclast survival. Ultrastructurally, apoptotic changes were
observed in detached cells and culture lysates exhibited elevated
caspase 3 activity, particularly in cultures lacking CSF-1.
DEVD-FMK (caspase 3 inhibitor) partially protected cells when combined
with OPGL, but not when used alone or in combination with
CSF-1. CSF-1 maintained NF-
B activation and increased the expression
of bcl-2 and bcl-XL mRNA, but had no effect on
JNK activation. In contrast, OPGL enhanced both NF-B
and JNK kinase activation and increased the expression of
c-src, but not bcl-2 and bcl-XL mRNA. These data
suggest that aspects of both OPGL’s and CSF-1’s signaling/survival
pathways are required for optimal osteoclast survival. In mice,
a single dose of OPG, the OPGL decoy receptor, led to a
>90% loss of osteoclasts because of apoptosis within 48 hours of
exposure without impacting osteoclast precursor cells.
Therefore, OPGL is essential, but not
sufficient, for osteoclast survival and endogenous CSF-1 levels
are insufficient to maintain osteoclast viability in the absence of
OPGL.
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