Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing.

Flick, Lisa M.; Weaver, Jason M.; Ulrich‐Vinther, Michael; Abuzzahab, Faruk; Zhang, Xinping; Dougall, William C.; Anderson, Dirk; O'Keefe, Regis J.; Schwarz, Edward M.

doi:10.1016/s0736-0266(03)00011-1

Cited by 82Bone Metabolism and DiseasesBone fractures and treatmentsBone health and osteoporosis research

The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.

Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing.

Open access

Flick, Lisa M., Weaver, Jason M., Ulrich‐Vinther, Michael, Abuzzahab, Faruk, Zhang, Xinping, Dougall, William C., Anderson, Dirk, O'Keefe, Regis J., Schwarz, Edward M.·2003·Journal of Orthopaedic Research

DOI 10.1016/s0736-0266(03)00011-1

Open this paper in CoChat — free account Open PDF

Abstract

As dominant regulators of osteoclastogenesis and bone resorption, receptor activator of NFκB (RANK), receptor activator of NFκB ligand, and OPG have been identified as ideal drug targets for the treatment of metabolic bone disease. One concern regarding the therapeutic use of RANK signaling inhibitors is their effect on fracture healing. Therefore we tested if uncoupling and osteoclast depletion via RANK blockade affects callus formation, maturation and matrix remodeling, as well as union rates in a mouse tibia fracture model. Low dose (1 mg/kg i.p.) RANK:Fc therapy had no effect on callus formation, matrix maturation and remodeling, and resulted in 100% bony union by day 28. High dose RANK:Fc treatment (10 mg/kg i.p.) effectively eliminated osteoclasts at the fracture site on day 14, with no significant effects on fracture healing. When therapy was discontinued, normal numbers of osteoclasts were observed at the fracture site by day 28. However, continuous therapy resulted in a large osteopetrotic callus consisting of both mineralized and unmineralized matrix that was void of osteoclasts, but bony union was unaffected at day 28. We also evaluated this process in the complete absence of RANK signaling using RANK ‐/‐ mice. These animals exhibited significant radiographic and histologic evidence of callus formation, indicating that RANK signaling is not required for fracture callus formation. However, only 33% of RANK ‐/‐ animals formed bony unions compared to 100% of the osteopetrotic control mice. This defect was most likely a result of decreased blood flow, as evidenced by fewer blood vessels in the RANK ‐/‐ animals. Together, these data imply that osteoclast depletion via inhibition of RANK signaling is a viable option for the treatment of pathological bone loss since no adverse effects on fracture healing are observed when therapy is discontinued. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/s0736-0266(03)00011-1

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Osteoclast numbers in fracture calluses returned to normal within 15 days after stopping RANK-Fc, and those animals also achieved union.
“Osteoclast numbers in fracture calluses were shown to return to normal levels within 15 d of stopping RANK-Fc treatment, and animals from this experimental group also achieved union.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [369]
RANK-Fc treatment in normal mice eliminated osteoclasts in long bone fracture calluses, but union occurred in all animals within 28 days.
“In this study, RANK-Fc treatment was associated with the elimination of osteoclasts in long bone fracture calluses, but union occurred in all animals within 28 d (369).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [369]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

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
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
Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL
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
Bone Resorption by Osteoclasts
Teitelbaum, S. L. (2000) · Science · doi:10.1126/science.289.5484.1504 · Cited by 3,962
OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis.
Kong, Y.-Y., Yoshida, H., Sarosi, I., Tan, H.-L., Timms, E., Capparelli, C., Morony, S., Oliveira-dos-Santos, A. J., Van, G., Itie, A., et al. (1999) · Nature · doi:10.1038/16852 · Cited by 3,351
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
Self-citation
Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.
Kong, Y.-Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., Morony, S., Capparelli, C., Li, J., Elliott, R., McCabe, S., et al. (1999) · Nature · doi:10.1038/46303 · Cited by 1,856
MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes
Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., Shapiro, S. D., Senior, R. M., & Werb, Z. (1998) · Cell · doi:10.1016/s0092-8674(00)81169-1 · Cited by 1,737
Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand.
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
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
Self-citation
The Cell and Molecular Biology of Fracture Healing
Einhorn, T. A. (1998) · Clinical Orthopaedics and Related Research · doi:10.1097/00003086-199810001-00003 · Cited by 1,280
The Roles of Osteoprotegerin and Osteoprotegerin Ligand in the Paracrine Regulation of Bone Resorption
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 1,185
RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism.
Li, J., Sarosi, I., Yan, X.-Q., Morony, S., Capparelli, C., Tan, H.-L., McCabe, S., Elliott, R., Scully, S., Van, G., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1566 · Cited by 1,119
Production of a standard closed fracture in laboratory animal bone
Bonnarens, F. O., & Einhorn, T. A. (1984) · Journal of Orthopaedic Research® · doi:10.1002/jor.1100020115 · Cited by 894
Fractures in adults
Rockwood, C. A., & Green, D. P. (1984) · Lippincott eBooks · Cited by 865
The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts.
Burgess, T. L., Qian, Y.-X., Kaufman, S., Ring, B. D., Van, G., Capparelli, C., Kelley, M., Hsu, H., Boyle, W. J., Dunstan, C. R., et al. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.145.3.527 · Cited by 689
Expression of osteoprotegerin, receptor activator of NF-κB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing.
Kon, T., Cho, T.-J., Aizawa, T., Yamazaki, M., Nooh, N., Graves, D., Gerstenfeld, L. C., & Einhorn, T. A. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.6.1004 · Cited by 552
Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord
Honoré, P., Luger, N. M., Sabino, M. A. C., Schwei, M. J., Rogers, S. D., Mach, D. B., O'keefe, P. F., Ramnaraine, M. L. R., Clohisy, D. R., & Mantyh, P. W. (2000) · Nature Medicine · doi:10.1038/74999 · Cited by 497
The effect of a single dose of osteoprotegerin in postmenopausal women.
Bekker, P. J., Holloway, D., Nakanishi, A., Arrighi, M., Leese, P. T., & Dunstan, C. R. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.2.348 · Cited by 484
Nonunion of the femoral diaphysis
Giannoudis, P. V., MacDonald, D. A., Matthews, S. J., Smith, R. M., Furlong, A. J., & de Boer, P. (2000) · Journal of Bone and Joint Surgery - British Volume · doi:10.1302/0301-620x.82b5.9899 · Cited by 413
Osteoclast Differentiation Factor Acts as a Multifunctional Regulator in Murine Osteoclast Differentiation and Function
Jimi, E., Akiyama, S., Tsurukai, T., Okahashi, N., Kobayashi, K., Udagawa, N., Nishihara, T., Takahashi, N., & Suda, T. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.1.434 · Cited by 404
Osteopetrosis, a New Recessive Skeletal Mutation on Chromosome 12 of the Mouse
Marks, S. C., & LANE, P. W. (1976) · Journal of Heredity · doi:10.1093/oxfordjournals.jhered.a108657 · Cited by 304
Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene
Kim, N., Odgren, P. R., Kim, D., Marks, S. C., & Choi, Y. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.200294797 · Cited by 299
Skeletal Renewal and Metabolic Bone Disease
Harris, W. H., & Heaney, R. P. (1969) · New England Journal of Medicine · doi:10.1056/nejm196901232800405 · Cited by 279
Effect of Nonsteroidal Antiinflammatory Drugs on Fracture Healing
Altman, R. D., Latta, L. L., Keer, R., Renfree, K. J., Hornicek, F. J., & Banovac, K. (1995) · Journal of Orthopaedic Trauma · doi:10.1097/00005131-199505000-00006 · Cited by 236
A standardized experimental fracture in the mouse tibia
Hiltunen, A., VUORIO, E. I., & Aro, H. T. (1993) · Journal of Orthopaedic Research® · doi:10.1002/jor.1100110219 · Cited by 208
Effect of alendronate on fracture healing and bone remodeling in dogs
Peter, C. P., Cook, W. O., Nunamaker, D. M., Provost, M. T., Seedor, J. G., & Rodan, G. A. (1996) · Journal of Orthopaedic Research® · doi:10.1002/jor.1100140113 · Cited by 185
Effect of bisphosphonate (Incadronate) on fracture healing of long bones in rats.
Li, J., Mori, S., Kaji, Y., Mashiba, T., Kawanishi, J., & Norimatsu, H. (1999) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1999.14.6.969 · Cited by 178
Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy.
Capparelli, C., Kostenuik, P. J., Morony, S., Starnes, C. O., Weimann, B., Van, G. Y., Scully, S. A., Qi, M., Lacey, D. L., & Dunstan, C. R. (2000) · PubMed · Cited by 147
In Vivo RANK Signaling Blockade Using the Receptor Activator of NF-κB:Fc Effectively Prevents and Ameliorates Wear Debris-Induced Osteolysis via Osteoclast Depletion Without Inhibiting Osteogenesis
Childs, L. M., Paschalis, E. P., Xing, L., Dougall, W. C., Anderson, D., Boskey, A. L., Puzas, J. E., Rosier, R. N., O’Keefe, R. J., Boyce, B. F., et al. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.2.192 · Cited by 143
Self-citation
Systemic corticosteroids inhibit bone healing in a rabbit ulnar osteotomy model
Waters, R. V., Gamradt, S. C., Asnis, P. D., VICKERY, B. H., Avnur, Z., Hill, E. L., & Bostrom, M. P. (2000) · Acta Orthopaedica Scandinavica · doi:10.1080/000164700317411951 · Cited by 129
Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy.
Oyajobi, B. O., Anderson, D. M., Traianedes, K., Williams, P. J., Yoneda, T., & Mundy, G. R. (2001) · PubMed · Cited by 119
Self-citation
Concentration of Bisphosphonate (Incadronate) in Callus Area and Its Effects on Fracture Healing in Rats
Li, J., Mori, S., Kaji, Y., Kawanishi, J., Akiyama, T., & Norimatsu, H. (2000) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2000.15.10.2042 · Cited by 94
Skeletal Renewal and Metabolic Bone Disease
Harris, W. H., & Heaney, R. P. (1969) · New England Journal of Medicine · doi:10.1056/nejm196901302800507 · Cited by 75
Breakthrough in bone: the molecular mechanism of osteoclast/osteoblast coupling revealed
Schwarz, E. M., & O’Keefe, R. J. (2000) · Current Opinion in Orthopedics · doi:10.1097/00001433-200010000-00001 · Cited by 17
Self-citation

Flagged first, then by citations

Research works printed but not linked: 1

Cruess RL, 1975, Fracture healing, Can J Surg, 18, 403

Sorted by citations

Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease
Kearns, A. E., Khosla, S., & Kostenuik, P. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0014 · Cited by 824
Unraveling macrophage contributions to bone repair
Wu, A. C., Raggatt, L. J., Alexander, K. A., & Pettit, A. R. (2013) · BoneKEy Reports · doi:10.1038/bonekey.2013.107 · Cited by 256
RANK Signaling Is Not Required for TNFα-Mediated Increase in CD11bhi Osteoclast Precursors but Is Essential for Mature Osteoclast Formation in TNFα-Mediated Inflammatory Arthritis
Li, P., Schwarz, E. M., O'Keefe, R. J., Ma, L., Boyce, B. F., & Xing, L. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.0301233 · Cited by 220
Self-citation
Osteoclasts are important for bone angiogenesis
Cackowski, F. C., Anderson, J. L., Patrene, K. D., Choksi, R. J., Shapiro, S. D., Windle, J. J., Blair, H. C., & Roodman, G. D. (2010) · Blood · doi:10.1182/blood-2009-08-237628 · Cited by 188
Osteoprotegerin treatment impairs remodeling and apparent material properties of callus tissue without influencing structural fracture strength.
Ulrich-Vinther, M., & Andreassen, T. T. (2005) · Calcified Tissue International · doi:10.1007/s00223-004-0126-9 · Cited by 46
Self-citation

An inhibitory role for caspase‐3 at the late stage of RANKL‐induced osteoclast differentiation in RAW264 cells and mouse bone marrow macrophages
Katao, Y., Shishido, M., Inami, K., Matsumoto, N., & Sawai, H. (2014) · Cell Biology International · doi:10.1002/cbin.10263 · Cited by 4
64Cu-RGD and microPET/CT as an imaging biomarker for osteoclast number in mouse models of negative and positive osteoclast regulation
Zheleznyak, A., Wadas, T. J., Sherman, C., et al. (2009) · Journal of Nuclear Medicine
The effects of tumor necrosis factor-α on osteoclast formation depend on the haematopoietic precursors
Portenier, J., Dolder, S., Wetterwald, A., et al. (2006) · Bone · doi:10.1016/j.bone.2006.01.113
Inhibitory Effect of Agrocybe Chaxingu (Chaxines) on RANKL-Induced Osteoclast Differentiation in RAW246.7 Cells: Possible Prevention of Osteoporosis
Konno, S., Elyaguov, J., Dixon, A., et al. (2022) · American Journal of Medical and Clinical Sciences · doi:10.33425/2832-4226/22005 · Cited by 1
RANKL as the master regulator of osteoclast differentiation
Takayanagi, H. (2021) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-020-01191-1 · Cited by 175

Authors: Flick, L. M., Weaver, J. M., Ulrich‐Vinther, M., Abuzzahab, F., Zhang, X., Dougall, W. C., Anderson, D., O'Keefe, R. J., & Schwarz, E. M.
Affiliations: University of Rochester Medicine (US)
Corresponding author: Flick, Lisa M.
Schwarz, Edward M.
ORCID: Weaver, Jason M.
Zhang, Xinping
Dougall, William C.
Schwarz, Edward M.
Venue: Journal of Orthopaedic Research
Publisher: Wiley
Published: 2003-07
Volume: 21
Issue: 4
Pages: 676-684
ISSN: 0736-0266 (ISSN-L)
1554-527X
DOI: 10.1016/s0736-0266(03)00011-1
OpenAlex: W2078086616
Cited by: 82
References: 35
Citations by year: 2026: 1 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 7 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 6 · 2014: 6 · 2013: 2 · 2012: 2
FWCI: 1.15
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 915 d)
Locations: Journal of Orthopaedic Research® (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r29ar044220-05)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-45791, AR 44220)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone fractures and treatments
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords: RANK signaling, fracture healing, osteoclasts, callus formation, bone remodeling, bony union, blood flow, bone resorption, metabolic bone disease
MeSH terms: Animals, Bony Callus, Glycoproteins, Cricetinae, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Mutant Strains, Osteoblasts, Osteoclasts, Recombinant Proteins, Regional Blood Flow, Tibial Fractures, Signal Transduction, NF-kappa B, CHO Cells, Fracture Healing, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Mice, Osteoprotegerin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing.

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks