Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity.
Abstract
Heparin is a highly sulfated glycosaminoglycan and has been shown to activate osteoclastic bone resorption though how is not yet clear. Here we investigate the molecule involved in heparin-induced activation of osteoclasts using an in vitro osteoclast culture assay. The formation and activation of osteoclasts are induced by receptor activator of NFkappaB ligand (RANKL) on osteoblasts, and inhibited by osteoprotegerin (OPG), a decoy receptor of RANKL, which is secreted from osteoblasts. In a coculture of mouse bone marrow cells and osteoblasts treated with 1,25-dihydroxyvitamin D(3) and prostaglandin E(2) on dentin slices, the bone marrow cells differentiate into osteoclasts, and resorption pits are formed on the dentin slices. Addition of heparin, various glycosaminoglycans, and chemically modified heparins to the coculture reveals that heparin enhances the pit-forming activity of osteoclasts, and this effect of heparin on the activation of osteoclasts is dependent on its sugar chain structure. By contrast, mRNA expression levels of RANKL, RANK, and OPG in the coculture are not altered by heparin treatment. Furthermore, neither RANK nor RANKL binds to heparin, suggesting that heparin does not directly interact with these proteins. Instead, heparin specifically binds to OPG and prevents OPG-mediated inhibition of osteoclastic bone resorption in the coculture. Heparin treatment does not enhance osteoclastic bone resorption in a monoculture of osteoclasts derived from bone marrow cells, and in the coculture using osteoblasts from OPG-deficient mice. A (125)I-OPG binding assay showed that OPG binds to osteoblasts and that this binding is inhibited by the addition of heparin, suggesting that OPG binds to RANKL on the osteoblast membrane and that heparin blocks this interaction. These results demonstrate that heparin enhances osteoclastic bone resorption by inhibiting OPG activity.
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OPG can bind membrane RANKL in a manner displaceable by soluble RANKL, and OPG might bind cell membrane glycosaminoglycans in a manner displaceable by heparin.
“OPG can bind to membrane RANKL in a manner that is displaceable by soluble RANKL (370), and OPG might also bind to cell membrane glycosaminoglycans in a manner that is displaceable by heparin (19).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [19]
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- Authors
- Irie, A., Takami, M., Kubo, H., Sekino-Suzuki, N., Kasahara, K., & Sanai, Y.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- SHOWA Medical University (JP)
- Takasaki University of Health and Welfare (JP)
- Corresponding author
- Irie, Atsushi
- Venue
- Bone
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 41
- Issue
- 2
- Pages
- 165-174
- ISSN
- 1873-2763 (ISSN-L)
- 8756-3282
- OpenAlex
- W2036679520
- Cited by
- 116
- References
- 53
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 12 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 5 · 2013: 12 · 2012: 5
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bone (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Keywords
- heparin, osteoclast resorption, osteoprotegerin, RANKL, RANK, glycosaminoglycans, osteoblasts, osteoclastogenesis
- MeSH terms
- Animals, Bone Marrow Cells, Bone Resorption, Cells, Cultured, Heparin, Humans, Mice, Inbred C57BL, Osteoblasts, Osteoclasts, Molecular Structure, Mice, Knockout, Coculture Techniques, Cell Culture Techniques, Mice, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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