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Receptor Activator of NF-κB and Osteoprotegerin Expression by Human Microvascular Endothelial Cells, Regulation by Inflammatory Cytokines, and Role in Human Osteoclastogenesis
Open accessAbstract
The receptor activator of NF-kappaB (RANKL) is the essential signal required for full osteoclast (OC) development, activation, and survival. RANKL is highly expressed in areas of trabecular bone remodeling and inflammatory bone loss, is increased on marrow stromal cells or osteoblasts by osteotropic hormones or cytokines, and is neutralized by osteoprotegerin (OPG), a soluble decoy receptor also crucial for preventing arterial calcification. Vascular endothelial cells (VEC) are critically involved in bone development and remodeling and influence OC recruitment, formation, and activity. Although OCs develop and function in close association with bone VEC and sinusoids, signals mediating their interactions are not well known. Here, we show for the first time that human microvascular endothelial cells (HMVEC) express transcripts for both RANKL and OPG; inflammatory cytokines tumor necrosis factor-alpha and interleukin-1alpha elevate RANKL and OPG expression 5-40-fold in HMVEC (with an early OPG peak that declines as RANKL rises), and RANKL protein increases on the surface of tumor necrosis factor-alpha-activated HMVEC. Cytokine-activated HMVEC promoted the formation, fusion, and bone resorption of OCs formed in co-cultures with circulating human monocytic precursors via a RANKL-mediated mechanism fully antagonized by exogenous OPG. Furthermore, paraffin sections of human osteoporotic fractured bone exhibited increased RANKL immunostaining in vivo on VEC located near resorbing OCs in regions undergoing active bone turnover. Therefore, cytokine-activated VEC may contribute to inflammatory-mediated bone loss via regulated production of RANKL and OPG. VEC-derived OPG may also serve as an autocrine signal to inhibit blood vessel calcification.
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“Osteoclastogenesis starts in the bone marrow upon the release of RANKL and macrophage colony-stimulating factor (M-CSF) from osteocytes and vascular endothelial cells close to the bone surface.138”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [138]
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Metadata
- Authors
- Collin-Osdoby, P., Rothe, L., Anderson, F., Nelson, M., Maloney, W., & Osdoby, P.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Osdoby, Philip
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 276
- Issue
- 23
- Pages
- 20659-20672
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2060482009
- Cited by
- 398
- References
- 57
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 12 · 2020: 10 · 2019: 5 · 2018: 10 · 2017: 13 · 2016: 10 · 2015: 24 · 2014: 15 · 2013: 12 · 2012: 25
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ar032927-12, AR32927)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK46547)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR32927)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- RANKL, osteoprotegerin, microvascular endothelial cells, osteoclastogenesis, TNF-α, interleukin-1 alpha, inflammatory cytokines, bone remodeling, bone resorption, osteoporosis, vascular calcification, RANK signaling
- MeSH terms
- Base Sequence, Bone Resorption, Cells, Cultured, Endothelium, Vascular, Gene Expression Regulation, Glycoproteins, Humans, Interleukin-1, Osteoclasts, RNA, Messenger, Tumor Necrosis Factor-alpha, Cytokines, DNA Primers, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Coculture Techniques, Osteoprotegerin
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