Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis.
Open accessAbstract
High systemic levels of osteoprotegerin (OPG) in OPG transgenic mice cause osteopetrosis with normal tooth eruption and bone elongation and inhibit the development and activity of endosteal, but not periosteal, osteoclasts. We demonstrate that both intravenous injection of recombinant OPG protein and transgenic overexpression of OPG in OPG−/2 mice effectively rescue the osteoporotic bone phenotype observed in OPG-deficient mice. However, intravenous injection of recombinant OPG over a 4-wk period could not reverse the arterial calcification observed in OPG−/− mice. In contrast, transgenic OPG delivered from mid-gestation through adulthood does prevent the formation of arterial calcification in OPG−/− mice. Although OPG is normally expressed in arteries, OPG ligand (OPGL) and receptor activator of NF-κB (RANK) are not detected in the arterial walls of wild-type adult mice. Interestingly, OPGL and RANK transcripts are detected in the calcified arteries of OPG−/− mice. Furthermore, RANK transcript expression coincides with the presence of multinuclear osteoclast-like cells. These findings indicate that the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes. Such findings may also explain the observed high clinical incidence of vascular calcification in the osteoporotic patient population.
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OPG deficiency is associated with poor bone quality; cortical bone collagen in OPG knockout mice has a woven rather than lamellar orientation, linked to elevated bone turnover.
“In addition to a deficit in bone quantity, OPG deficiency is associated with poor bone quality as well.Collagen within the cortical bone of OPG knockout mice has a woven rather than lamellar orientation, a phenomenon that is associated with pathologically elevated bone turnover (127).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [127]
Vascular calcification in OPG knockout animals can be prevented by transgenic overexpression of soluble OPG, indicating systemic RANKL inhibition can prevent vascular consequences of endogenous OPG deficiency.
“This vascular calcification could be prevented via transgenic overexpression of soluble OPG, indicating that systemic RANKL inhibition could prevent the vascular consequences of endogenous OPG deficiency (127).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [127]
OPG therapy consistently suppresses vascular calcification in animal models, but data on its effects on atherogenesis or other vascular disease aspects are minimal.
“Although OPG therapy consistently suppresses vascular calcification in animal models (127, 144, 166), there are minimal data on the effects of OPG therapy on atherogenesis or other aspects of vascular disease.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [127]
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- Authors
- Min, H., Morony, S., Sarosi, I., Dunstan, C. R., Capparelli, C., Scully, S., Van, G., Kaufman, S., Kostenuik, P. J., Lacey, D. L., Boyle, W. J., & Simonet, W. S.
- Affiliations
- Amgen (United States) (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2000-08-14
- Volume
- 192
- Issue
- 4
- Pages
- 463-474
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2193236
- OpenAlex
- W2156467557
- Cited by
- 550
- References
- 32
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 10 · 2023: 9 · 2022: 10 · 2021: 17 · 2020: 23 · 2019: 18 · 2018: 12 · 2017: 27 · 2016: 14 · 2015: 27 · 2014: 17 · 2013: 20 · 2012: 25
- FWCI
- 7.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Keywords
- osteoprotegerin, osteoporosis, vascular calcification, osteoclasts, osteoclastogenesis, RANK, RANK ligand, arterial calcification, bone resorption, osteopetrosis
- MeSH terms
- Tartrate-Resistant Acid Phosphatase, Acid Phosphatase, Animals, Aorta, Calcinosis, Cathepsins, Femur, Glycoproteins, Cricetinae, Humans, Immunohistochemistry, Isoenzymes, Mice, Transgenic, Osteoclasts, Osteopetrosis, Osteoporosis, Radiography, Recombinant Fusion Proteins, Blotting, Western, Bone Density, NF-kappa B, CHO Cells, In Situ Hybridization, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Mice, Osteoprotegerin, Cathepsin K
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