Platelet dysfunction and a high bone mass phenotype in a murine model of platelet-type von Willebrand disease.

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.

• Authors: Larry J Suva, Eric Hartman, Joshua D Dilley, Susan Russell, Nisreen S Akel, Robert A Skinner, William R Hogue, Ulrich Budde, Kottayil I Varughese, Taisuke Kanaji, Jerry Ware
• Journal: The American journal of pathology (Am J Pathol) Vol. 172 Issue 2 Pg. 430-9 (Feb 2008) ISSN: 0002-9440 [Print] United States
• PMID: 18187573 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Platelet Glycoprotein GPIb-IX Complex
• von Willebrand Factor

Topics

• Animals
• Bleeding Time
• Blood Platelet Disorders (genetics, physiopathology)
• Blood Platelets (physiology)
• Bone and Bones (pathology, physiology)
• Cell Differentiation
• Disease Models, Animal
• Flow Cytometry
• Humans
• Mice
• Mice, Transgenic
• Osteoclasts (cytology)
• Phenotype
• Platelet Glycoprotein GPIb-IX Complex (chemistry, genetics)
• Protein Binding
• Protein Structure, Secondary
• Splenomegaly (etiology)
• Thrombopoiesis (physiology)
• von Willebrand Diseases (genetics, physiopathology)
• von Willebrand Factor (chemistry, genetics)