The Ratio of Messenger RNA Levels of Receptor Activator of Nuclear Factor κB Ligand to Osteoprotegerin Correlates with Bone Remodeling Indices in Normal Human Cancellous Bone but Not in Osteoarthritis
Open accessAbstract
The determinants of cancellous bone turnover and trabecular structure are not understood in normal bone or skeletal disease. Bone remodeling is initiated by osteoclastic resorption followed by osteoblastic formation of new bone. Receptor activator of nuclear factor κB ligand (RANKL) is a newly described regulator of osteoclast formation and function, the activity of which appears to be a balance between interaction with its receptor RANK and with an antagonist binding protein osteoprotegerin (OPG). Therefore, we have examined the relationship between the expression of RANKL, RANK, and OPG and indices of bone structure and turnover in human cancellous bone from the proximal femur. Bone samples were obtained from individuals with osteoarthritis (OA) at joint replacement surgery and from autopsy controls. Histomorphometric analysis of these samples showed that eroded surface (ES/BS) and osteoid surface (OS/BS) were positively associated in both control (p < 0.001) and OA (p < 0.02), indicating that the processes of bone resorption and bone formation remain coupled in OA, as they are in controls. RANKL, OPG, and RANK messenger RNA (mRNA) were abundant in human cancellous bone, with significant differences between control and OA individuals. In coplotting the molecular and histomorphometric data, strong associations were found between the ratio of RANKL/OPG mRNA and the indices of bone turnover (RANKL/OPG vs. ES/BS: r = 0.93, p < 0.001; RANKL/OPG vs. OS/BS: r = 0.80, p < 0.001). These relationships were not evident in trabecular bone from severe OA, suggesting that bone turnover may be regulated differently in this disease. We propose that the effective concentration of RANKL is related causally to bone turnover.
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Osteoclast activity likely depends at least in part on the relative balance between RANKL and OPG.
“Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [87]
In cadaveric proximal femur bone biopsies, the RANKL/OPG mRNA ratio was strongly associated with histomorphometric indices of bone turnover in trabecular bone.
“In a separate study of cadaveric proximal femur bone biopsies, RANKL/ OPG mRNA ratio was strongly associated with histomorphometric indices of bone turnover in trabecular bone (87).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [87]
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Cites
Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
Lacey, D. L., Timms, E., Tan, H.-L., Kelley, M. J., Dunstan, C. R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81569-x · Cited by 5,439 · see citing works
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.
Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M.-S., Lüthy, R., Nguyen, H. Q., Wooden, S., Bennett, L., Boone, T., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80209-3 · Cited by 5,130 · see citing works
Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S.-I., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.7.3597 · Cited by 4,224 · see citing works
Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.
Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., Capparelli, C., Scully, S., Tan, H. L., Xu, W., Lacey, D. L., et al. (1998) · Genes & Development · doi:10.1101/gad.12.9.1260 · Cited by 2,483 · see citing works
A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function.
Anderson, D. M., Maraskovsky, E., Billingsley, W. L., Dougall, W. C., Tometsko, M. E., Roux, E. R., Teepe, M. C., DuBose, R. F., Cosman, D., & Galibert, L. (1997) · Nature · doi:10.1038/36593 · Cited by 2,290 · see citing works
Hsu, H., Lacey, D. L., Dunstan, C. R., Solovyev, I., Colombero, A., Timms, E., Tan, H.-L., Elliott, G., Kelley, M. J., Sarosi, I., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3540 · Cited by 1,636 · see citing works
RANK is essential for osteoclast and lymph node development.
Dougall, W. C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M. E., Maliszewski, C. R., et al. (1999) · Genes & Development · doi:10.1101/gad.13.18.2412 · Cited by 1,478 · see citing works
Hofbauer, L. C., Khosla, S., Dunstan, C. R., Lacey, D. L., Boyle, W. J., & Riggs, B. L. (2000) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2000.15.1.2 · Cited by 1,167 · see citing works
Wong, B. R., Rho, J., Arron, J. R., Robinson, E. A., Orlinick, J. R., Chao, M. V., Kalachikov, S. M., Cayani, E., Bartlett, F. S., Frankel, W. N., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.40.25190 · Cited by 1,042 · see citing works
Parfitt, A. M. (1994) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240550303 · Cited by 1,001 · see citing works
Hofbauer, L. C., Gori, F., Riggs, B. L., Lacey, D. L., Dunstan, C. R., Spelsberg, T. C., & Khosla, S. (1999) · Endocrinology · doi:10.1210/endo.140.10.7034 · Cited by 794 · see citing works
Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S.-I., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., et al. (1998) · Cited by 650 · see citing works
ROLE OF MECHANICAL FACTORS IN PATHOGENESIS OF PRIMARY OSTEOARTHRITIS
Radin, E., Paul, I., & Rose, R. (1972) · The Lancet · doi:10.1016/s0140-6736(72)90179-1 · Cited by 595 · see citing works
Li, B., & Aspden, R. M. (1997) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1997.12.4.641 · Cited by 461 · see citing works
Horwood, N. J., Elliott, J., Martin, T. J., & Gillespie, M. T. (1998) · Endocrinology · doi:10.1210/endo.139.11.6433 · Cited by 456 · see citing works
Radiographic osteoarthritis of the hip and bone mineral density
Nevitt, M. C., Lane, N. E., Scott, J. C., et al. (1995) · Arthritis & Rheumatism · doi:10.1002/art.1780380706 · Cited by 364 · see citing works
Kartsogiannis, V., Zhou, H., Horwood, N. J., Thomas, R. J., Hards, D. K., Quinn, J. M. W., Niforas, P., Ng, K. W., Martin, T. J., & Gillespie, M. T. (1999) · Bone · doi:10.1016/s8756-3282(99)00214-8 · Cited by 324 · see citing works
Takai, H., Kanematsu, M., Yano, K., Tsuda, E., Higashio, K., Ikeda, K., Watanabe, K., & Yamada, Y. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.42.27091 · Cited by 299 · see citing works
The Pathology of Articular and Spinal Diseases.
&NA; (1950) · The American Journal of the Medical Sciences · doi:10.1097/00000441-195022040-00015 · Cited by 216 · see citing works
Expression of Osteoclast Differentiation Signals by Stromal Elements of Giant Cell Tumors
Atkins, G. J., Haynes, D. R., Graves, S. E., Evdokiou, A., Hay, S. J., Bouralexis, S., & Findlay, D. M. (2000) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2000.15.4.640 · Cited by 197 · see citing works
Self-citationDequeker, J., Mohan, S., Finkelman, R. D., et al. (1993) · Arthritis & Rheumatism · doi:10.1002/art.1780361209 · Cited by 191 · see citing works
Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity
Martin, T. J., & Ng, K. W. (1994) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240560312 · Cited by 173 · see citing works
Bland, J. H., & Cooper, S. M. (1984) · Seminars in Arthritis and Rheumatism · doi:10.1016/0049-0172(84)90002-7 · Cited by 114 · see citing works
Interleukins in the Control of Osteoclast Differentiation
Martin, T. J., Romas, E., & Gillespie, M. T. (1998) · Critical Reviews in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v8.i2.10 · Cited by 111 · see citing works
INVERSE RELATIONSHIP OSTEOARTHRITIS—OSTEOPOROSIS: WHAT IS THE EVIDENCE? WHAT ARE THE CONSEQUENCES?
Dequeker, J., Boonen, S., Aerssens, J., & Westhovens, R. (1996) · Lara D. Veeken · doi:10.1093/rheumatology/35.9.813 · Cited by 111 · see citing works
Boyce, R. W., Paddock, C. L., Gleason, J. R., Sletsema, W. K., & Eriksen, E. F. (1995) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.5650100207 · Cited by 99 · see citing works
Femoral Trabecular Bone of Osteoarthritic and Normal Subjects in an Age and Sex Matched Group
Fazzalari, N. L., & Parkinson, I. H. (1998) · Osteoarthritis and Cartilage · doi:10.1053/joca.1998.0141 · Cited by 80 · see citing works
Self-citationKuliwaba, J. S., Findlay, D. M., Atkins, G. J., et al. (2000) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2000.15.2.332 · Cited by 50 · see citing works
Self-citationFazzalari, N. L., Darracott, J., & Vernon-Roberts, B. (1985) · Bone · doi:10.1016/8756-3282(85)90044-4 · Cited by 50 · see citing works
Self-citationNuclear antigen histone H1 is primarily involved in lupus erythematosus cell formation
Schett, G. A., Steiner, G. E., & Smolen, J. S. (1998) · Arthritis & Rheumatism · doi:10.1002/1529-0131(199808)41:8 · Cited by 44 · see citing works
Age-Related Changes in Femoral Trabecular Bone in Arthrosis
Crane, G. J., Fazzalari, N. L., Parkinson, I. H., et al. (1990) · Acta Orthopaedica Scandinavica · doi:10.3109/17453679008993554 · Cited by 35 · see citing works
Self-citationRemodelling of subchondral bone in osteoarthritis: a histomorphometric study.
Amir, G., Pirie, C. J., Rashad, S., et al. (1992) · Journal of Clinical Pathology · doi:10.1136/jcp.45.11.990 · Cited by 32 · see citing works
Comparative study of iliac crest and subchondral femoral bone in osteoarthritic patients
Fazzalari, N. L., Moore, R. J., Manthey, B. A., et al. (1992) · Bone · doi:10.1016/8756-3282(92)90079-c · Cited by 31 · see citing works
Self-citation
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Cited by
Sorted by citations
Kearns, A. E., Khosla, S., & Kostenuik, P. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0014 · Cited by 824 · see citing works
Osteoporosis, inflammation and ageing
Ginaldi, L., Di Benedetto, M. C., & De Martinis, M. (2005) · Immunity & Ageing · doi:10.1186/1742-4933-2-14 · Cited by 412 · see citing works
Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength.
KOSTENUIK, P. (2005) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2005.06.005 · Cited by 281 · see citing works
RANKL Expression Is Related to the Differentiation State of Human Osteoblasts
Atkins, G. J., Kostakis, P., Pan, B., Farrugia, A., Gronthos, S., Evdokiou, A., Harrison, K., Findlay, D. M., & Zannettino, A. C. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.6.1088 · Cited by 245 · see citing works
Self-citationExpression of RANKL and OPG correlates with age-related bone loss in male C57BL/6 mice.
Cao, J., Venton, L., Sakata, T., & Halloran, B. P. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.2.270 · Cited by 173 · see citing works
Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover.
Indridason, O. S., Franzson, L., & Sigurdsson, G. (2005) · Osteoporosis International · doi:10.1007/s00198-004-1699-x · Cited by 107 · see citing works
Tsangari, H., Findlay, D. M., Kuliwaba, J. S., Atkins, G. J., & Fazzalari, N. L. (2004) · Bone · doi:10.1016/j.bone.2004.02.006 · Cited by 69 · see citing works
Self-citationAlvarez, L., Peris, P., Guañabens, N., Vidal, S., Ros, I., Pons, F., Filella, X., Monegal, A., Muñoz‐Gomez, J., & Ballesta, A. M. (2003) · Arthritis & Rheumatism · doi:10.1002/art.10834 · Cited by 66 · see citing works
Increased RANKL/OPG mRNA Ratio in Iliac Bone Biopsies From Women with Hip Fractures
Abdallah, B. M., Stilgren, L. S., Nissen, N., Kassem, M., Jørgensen, H. R. I., & Abrahamsen, B. (2005) · Calcified Tissue International · doi:10.1007/s00223-004-0074-4 · Cited by 60 · see citing works
- Authors
- Fazzalari, N. L., Kuliwaba, J. S., Atkins, G. J., Forwood, M. R., & Findlay, D. M.
- Affiliations
- South Australia Pathology (AU)
- Royal Adelaide Hospital (AU)
- The University of Queensland (AU)
- Corresponding author
- Fazzalari, Nicola L.
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-06-01
- Volume
- 16
- Issue
- 6
- Pages
- 1015-1027
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2019917228
- Cited by
- 129
- References
- 34
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 6 · 2012: 5
- FWCI
- 2.21
- 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)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Arthritis Foundation
- Arthritis Foundation of Australia
- Royal Adelaide Hospital
- 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 › Rheumatoid Arthritis Research and Therapies
- Keywords
- RANKL, osteoprotegerin, RANK, bone remodeling, bone turnover, osteoarthritis, trabecular bone, osteoclastogenesis, mRNA expression, histomorphometry, proximal femur, bone resorption, bone formation
- MeSH terms
- Adult, Age Factors, Aged, Aged, 80 and over, Carrier Proteins, Female, Femur, Glycoproteins, Humans, Male, Membrane Glycoproteins, Middle Aged, Osteoarthritis, Reference Values, RNA, Messenger, Gene Expression, Case-Control Studies, Bone Remodeling, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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