Cited by 75Platelet Disorders and TreatmentsBone Metabolism and DiseasesBlood Coagulation and Thrombosis Mechanisms

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

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Suva, Larry J., Hartman, Eric, Dilley, Joshua D., Russell, Susan, Akel, Nisreen S., Skinner, Robert A., Hogue, William R., Budde, Ulrich +3 more·2008·The American Journal of Pathology

Abstract

The platelet glycoprotein Ib-IX receptor binds surface-bound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass.

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Registry

Crossref · 10.2353/ajpath.2008.070417

Cites

58 of 58 references verified0 citation errors · 0 not checkable

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  • Transgenic mice expressing a mutant form of VWF corresponding to platelet-type von Willebrand disease exhibit a high bone mass phenotype.

    “Although mice lacking VWF have been reported to have normal bone density (36), transgenic mice expressing a mutant form of the protein corresponding to that seen in patients with platelet-type von Willebrand disease exhibit a high bone mass phenotype (37).”

    From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [37]

    The paper’s ‘High Bone Mass Phenotype as a Consequence of the G233V Mutation’ section reports increased bone volume in the transgenic mice. But the introductory passage identifies the expressed mutation as G233V in the platelet GP Ibα receptor, not in VWF. The bone-mass finding is supported; the mutant protein is misidentified. (LLM, conf=0.90)

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Cites

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Research works printed but not linked: 3

  1. Andrews RK, Gardiner EE, Shen Y, Whisstock JC, Berndt MC: Gly- coprotein Ib-IX-V. Int J Biochem Cell Biol 2003, 35:1170 -1174
  2. Skinner R, Hickmon S, Lumpkin CJ, Aronson J, Nicholas R: Twenty years of successful specimen management. J Histotechnol 1997, 20:267-277
  3. Huizinga EG, Tsuji S, Romijn RA, Schiphorst ME, de Groot PG, Sixma JJ, Gros P: Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science 2002, 297:1176 -1179

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Authors
Suva, L. J., Hartman, E., Dilley, J. D., Russell, S., Akel, N. S., Skinner, R. A., Hogue, W. R., Budde, U., Varughese, K. I., Kanaji, T., & Ware, J.
Affiliations
  • University of Arkansas for Medical Sciences (US)
  • Kurume University (JP)
Corresponding author
Ware, Jerry
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2008-02
Volume
172
Issue
2
Pages
430-439
ISSN
0002-9440 (ISSN-L)
OpenAlex
W2093228291
Cited by
75
References
58
Citations by year
2026: 4 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 5
FWCI
3.92
Type
journal article
Language
en
Open access
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL50541)
Topics
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords
platelet-type von Willebrand disease, von Willebrand factor, mouse model, high bone mass, trabecular bone volume, bone resorption, osteoclasts, osteoblastogenesis, megakaryopoiesis, splenomegaly, bone strength
MeSH terms
Animals, Bleeding Time, Blood Platelet Disorders, Blood Platelets, Bone and Bones, Cell Differentiation, Disease Models, Animal, Flow Cytometry, Humans, Mice, Transgenic, Osteoclasts, Phenotype, Protein Binding, Splenomegaly, von Willebrand Factor, von Willebrand Diseases, Protein Structure, Secondary, Platelet Glycoprotein GPIb-IX Complex, Thrombopoiesis, Mice

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