Osteoprotegerin Ligand Modulates Murine Osteoclast Survival in Vitro and in Vivo

• Published in: The American journal of pathology Vol. 157; no. 2; pp. 435 - 448
• Main Authors: Lacey, David L., Tan, Hong Lin, Lu, John, Kaufman, Steven, Van, Gwyneth, Qiu, Wanrang, Rattan, Alana, Scully, Sheila, Fletcher, Frederick, Juan, Todd, Kelley, Michael, Burgess, Teresa L., Boyle, William J., Polverino, Anthony J.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-08-2000; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Apoptosis - drug effects; bcl-X Protein; Biological and medical sciences; Carrier Proteins - pharmacology; Cell Survival - drug effects; Cells, Cultured; Diseases of the osteoarticular system; Gene Expression Regulation - drug effects; Glycoproteins - pharmacology; Injections, Subcutaneous; Macrophage Colony-Stimulating Factor - pharmacology; Male; Medical sciences; Membrane Glycoproteins - pharmacology; Mice; Mice, Inbred C3H; Miscellaneous. Osteoarticular involvement in other diseases; NF-kappa B - metabolism; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - ultrastructure; Osteoprotegerin; Proto-Oncogene Proteins c-bcl-2 - genetics; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Regular; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Space life sciences; Time Factors; Immunohistochemistry; Cell culture; Ligand; Pathogenesis; Cytokine; Rodentia; Diseases of the osteoarticular system; Resorption; Bone disease; Osteoclast; Bone remodeling; Electron microscopy; Colony stimulating factor; In vitro; Pathology; In vivo; Vertebrata; Mammalia; Mouse; Tumor necrosis factor; Animal; Bone; Molecular biology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)64556-7

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-κB activation and increased the expression of bcl-2 and bcl-X
L mRNA, but had no effect on JNK activation. In contrast, OPGL enhanced both NF-κB and JNK kinase activation and increased the expression of c-src, but not bcl-2 and bcl-X
L 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.