RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis.
Open accessAbstract
RANKL is an essential mediator of bone erosions, but the role of RANKL in systemic bone loss had not been studied in arthritis. RANKL protein was increased in rat joint extracts and serum at the earliest stages of arthritis. Osteoprotegerin (OPG) treatment reversed local and systemic bone loss, suggesting that RANKL is both a marker and mediator of bone loss in arthritis. Introduction: RANKL is well established as an essential mediator of bone erosions in inflammatory arthritis, but the role of RANKL in systemic bone loss in arthritis had not been studied. We hypothesized that serum RANKL could serve as both a mediator and as a novel biomarker for local and systemic bone loss in arthritis. We challenged this hypothesis in two established rat models of inflammatory arthritis. We sought to determine whether serum RANKL was elevated early in disease progression and whether RANKL suppression could prevent both local and systemic bone loss in these models. Materials and Methods: Detailed time-course studies were conducted in animals with collagen-induced (CIA) or adjuvant-induced (AIA) arthritis to evaluate the onset and progression of inflammation (paw swelling), bone erosions, osteoclast numbers, and RANKL protein levels in arthritic joints and in serum. Additional CIA and AIA rats (n = 8/group) received placebo (PBS) or recombinant OPG (3 mg/kg three times weekly) for 10 days beginning 4 days after disease onset (first macroscopic evidence of hind paw erythema and edema) to assess the role of RANKL in local and systemic bone loss. Results: RANKL protein was significantly elevated in the joints and serum of CIA and AIA rats within 1–2 days of disease onset. Increased RANKL levels were associated with local (hind paw) and systemic (vertebral) osteopenia in both models. The RANKL inhibitor OPG prevented local and systemic osteopenia in both models of established disease. Conclusions: RANKL protein is significantly increased both locally and systemically during the earliest stages of inflammatory arthritis in rats, suggesting that serum RANKL might have prognostic value for bone erosions and systemic osteopenia in this condition. RANKL inhibition through OPG prevented local and systemic bone loss in these arthritis models, suggesting that RANKL inhibition is a promising new approach for treating bone loss in arthritis.
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Both soluble and membrane-bound forms of RANKL expressed by T cells are implicated in focal bone erosions in inflammatory arthritis.
“T Cells express both soluble and membrane-bound forms of RANKL (49,50), and both forms are implicated in focal bone erosions associated with inflammatory arthritis (26,49).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [26]
In adjuvant and collagen-induced rat arthritis models, RANKL protein levels increased before or simultaneous with the earliest bone erosions and osteoclast responses.
“RANKL protein levels were significantly increased before or simultaneous with the earliest appearance of bone erosions and osteoclast responses (26).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [26]
Animal models of rheumatoid arthritis consistently show up-regulation of RANKL in inflamed joints.
“Animal models of RA consistently show up-regulation of RANKL in inflamed joints (26,49,181,225,229,230)”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [26]
Recombinant OPG treatment suppresses bone erosions and osteoclasts in several rodent arthritis models, including adjuvant arthritis, collagen-induced arthritis, and TNF-mediated arthritis.
“RANKL inhibition via recombinant OPG treatment also results in marked suppression of bone erosions and osteoclasts in several rodent models, including adjuvant arthritis (26,49,177,232,233), collagen-induced arthritis (26,181,233), and TNF-mediated arthritis (136, 234).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [26]
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References 49 · Cited by 99
- Authors
- Stolina, M., Adamu, S., Ominsky, M., Dwyer, D., Asuncion, F., Geng, Z., Middleton, S., Brown, H., Pretorius, J., Schett, G., Bolon, B., Feige, U., Zack, D., & Kostenuik, P. J.
- Affiliations
- Amgen (United States) (US)
- Medical University of Vienna (AT)
- Corresponding author
- Kostenuik, Paul J
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-10-01
- Volume
- 20
- Issue
- 10
- Pages
- 1756-1765
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2033937368
- Cited by
- 99
- References
- 49
- Citations by year
- 2026: 1 · 2022: 1 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 6 · 2014: 6 · 2013: 6 · 2012: 7
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- 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 › Osteoarthritis Treatment and Mechanisms
- Keywords
- RANKL, osteoprotegerin, inflammatory arthritis, systemic bone loss, osteopenia, bone erosion, collagen-induced arthritis, adjuvant-induced arthritis, osteoclasts, serum biomarkers, RANKL inhibition, rat model
- MeSH terms
- Animals, Arthritis, Experimental, Bone Diseases, Metabolic, Carrier Proteins, Disease Models, Animal, Female, Glycoproteins, Inflammation, Joints, Male, Membrane Glycoproteins, Rats, Inbred Lew, Biomarkers, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Rats, Osteoprotegerin, RANK Ligand
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