Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo

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 + co lony-stimulating factor-1 (CSF-1) is required for optimal osteoclast surviv al. Ultrastructurally, apoptotic changes were observed in detached cells an d culture lysates exhibited elevated caspase 3 activity, particularly in cu ltures lacking CSF-1, DEVD-FMK (caspase 3 inhibitor) partially protected ce lls when combined with OPGL, but not when used alone or in combination with CSF-1. CSF-1 maintained NF-kappa B activation and increased the expression of bcl-2 and bcl-X-L mRNA, but had no effect on JNK activation. In contras t, OPGL enhanced both NF-kappa B and JNK kinase activation and increased th e expression of c-src, but not bcl-2 and bcl-X-L mRNA, These data suggest t hat aspects of both OPGL's and CSF-1's signaling/survival pathways are requ ired for optimal osteoclast survival. In mice, a single dose of OPG, the OP GL decoy receptor, led to a >90% loss of osteoclasts because of apoptosis w ithin 48 hours of exposure without impacting osteoclast precursor cells. Th erefore, 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.