Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo.
Open accessAbstract
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-kappaB 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-kappaB 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.
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OPG/OCIF suppresses osteoclastogenesis in vitro and also suppresses osteoclast activity, survival, and adhesion to bone surfaces.
“This molecule was referred to as osteoclastogenesis inhibitory factor (OCIF) based on its ability to suppress osteoclastogenesis in vitro (5).OPG/OCIF was shown soon thereafter to also suppress osteoclast activity (7)(8)(9), survival (10,11), and adhesion to bone surfaces (12,13).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [11]
Prolonged osteoclast suppression with OPG-Fc is probably due to the drug's long circulating half-life and the time needed to regenerate osteoclasts from precursors after clearance.
“The prolonged duration of osteoclast suppression with OPG-Fc treatment was probably related to the long circulating half-life of the drug (24), as well as the time required to regenerate new osteoclasts from their precursor population once the drug is cleared (11).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [11]
Reduced osteoclast numbers in mice after OPG-Fc are attributable to osteoclast apoptosis, seen histologically within 6 hours.
“Reduced osteoclast numbers in mice was attributable to osteoclast apoptosis, which was apparent histologically within 6 h of OPG-Fc treatment (11).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [11]
OPG-Fc treatment rapidly reduces osteoclast numbers in mice and rats by 50-60% within 12-24 hours.
“OPG suppression of osteoclast numbers in mice and rats also occurs rapidly, with 50 -60% reductions in osteoclasts noted within 12-24 h of treatment with an OPG-Fc fusion protein (11,24).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [11]
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- Authors
- Lacey, D. L., Tan, H. L., Lu, J., Kaufman, S., Van, G., Qiu, W., Rattan, A., Scully, S., Fletcher, F., Juan, T., Kelley, M., Burgess, T. L., Boyle, W. J., & Polverino, A. J.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Lacey, David L.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2000-08
- Volume
- 157
- Issue
- 2
- Pages
- 435-448
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1850124
- OpenAlex
- W2133551420
- Cited by
- 391
- References
- 33
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 9 · 2021: 10 · 2020: 12 · 2019: 23 · 2018: 7 · 2017: 10 · 2016: 15 · 2015: 10 · 2014: 7 · 2013: 27 · 2012: 25
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- osteoprotegerin ligand, osteoclast survival, colony-stimulating factor 1, osteoclast apoptosis, caspase-3, NF-κB activation, JNK activation, Bcl-2, Bcl-xL, Src kinase, osteoprotegerin, bone resorption, osteoclastogenesis
- MeSH terms
- Animals, Carrier Proteins, Cell Survival, Cells, Cultured, Gene Expression Regulation, Glycoproteins, Injections, Subcutaneous, Male, Membrane Glycoproteins, Mice, Inbred C3H, Osteoclasts, RNA, Messenger, Time Factors, Macrophage Colony-Stimulating Factor, NF-kappa B, Apoptosis, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Proto-Oncogene Proteins c-bcl-2, bcl-X Protein, Mice, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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