Osteoprotegerin Reduces Osteoclast Numbers and Prevents Bone Erosion in Collagen-Induced Arthritis
Open accessAbstract
Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though synovitis is not affected. These findings indicate the potential utility of disrupting RANK signaling to preserve skeletal integrity in inflammatory arthritis.
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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 [181]
Other arthritis models confirmed that OPG or RANKL ablation preserves cartilage, measured histologically by proteoglycan preservation.
“Other arthritis models have confirmed the ability of OPG or RANKL ablation to preserve cartilage, as measured histologically by proteoglycan preservation (110, 177, 181).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [181]
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- Authors
- Romas, E., Sims, N. A., Hards, D. K., Lindsay, M., Quinn, J. W. M., Ryan, P. F. J., Dunstan, C. R., Martin, T. J., & Gillespie, M. T.
- Affiliations
- The University of Melbourne (AU)
- St Vincents Institute of Medical Research (AU)
- Monash University (AU)
- Amgen (United States) (US)
- Corresponding author
- Romas, Evan
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 161
- Issue
- 4
- Pages
- 1419-1427
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1867274
- OpenAlex
- W2032384549
- Cited by
- 368
- References
- 44
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 9 · 2019: 8 · 2018: 7 · 2017: 1 · 2016: 5 · 2015: 17 · 2014: 12 · 2013: 3 · 2012: 16
- FWCI
- 19.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Arthritis Foundation
- Arthritis Foundation of Australia
- National Health and Medical Research Council
- 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 › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- osteoprotegerin, collagen-induced arthritis, rheumatoid arthritis, osteoclasts, bone erosion, RANK ligand, RANK signaling, joint destruction, cartilage destruction, synovitis
- MeSH terms
- Animals, Arthritis, Experimental, Bone Diseases, Carrier Proteins, Collagen, Glycoproteins, Membrane Glycoproteins, Osteoclasts, Time Factors, Transcription, Genetic, Tumor Necrosis Factor-alpha, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Rats, Osteoprotegerin, RANK Ligand
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