Published online before print January 10, 2008

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(American Journal of Pathology. 2008;172:430-439.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070417

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

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 and Jerry Ware^*

From the Departments of Physiology and Biophysics^*and Orthopaedic Surgery,Center for Orthopedic Research, Barton Research Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas; the Coagulation Laboratory,Laboratory Association Professor Arndt and Partners, Hamburg, Germany; and the Department of Medicine,Division of Hematology, Kurume University School of Medicine, Fukuoka, Japan

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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