Dissection of platelet and myeloid cell defects by conditional targeting of the β3-integrin subunit

The purpose of this work was to determine platelet and myeloid cell-specific requirements for beta 3-containing integrins in hemostasis, bone resorption, and tumor growth. LoxP-flanked mice were generated to study the conditional deletion of beta 3-integrin in platelets [knockout in platelets (KOP)] and myeloid cells [knockout in myeloid (KOM)]. Using the beta 3KOP and beta 3KOM strains of mice, we studied the role of beta 3-integrin in hemostasis, bone resorption, and subcutaneous tumor growth. Tissue-specific deletion of platelet beta 3-integrins in beta 3KOP mice did not affect bone mass but resulted in a severe bleeding phenotype. No growth difference of tumor xenografts or in neoangiogenesis were found in beta 3KOP mice, in contrast to the defects observed in germline beta 3(-/-) mice. Conditional deletion of myeloid beta 3-integrins in beta 3KOM mice resulted in osteopetrosis but had no effect on hemostasis or mortality. Tumor growth in beta 3KOM mice was increased and accompanied by decreased macrophage infiltration, without increase in blood vessel number. Platelet beta 3-integrin deficiency was sufficient to disrupt hemostasis but had no effect on bone mass or tumor growth. Myeloid-specific beta 3-integrin deletion was sufficient to perturb bone mass and enhance tumor growth due to reduced macrophage infiltration in the tumors. These results suggest that beta 3-integrins have cell-specific roles in complex biological processes.-Morgan, E. A., Schneider, J. G., Baroni, T. E., Uluckan, O., Heller, E., Hurchla, M. A., Deng, H., Floyd, D., Berdy, A., Prior, J. L., Piwnica-Worms, D., Teitelbaum, S. L., Ross, F. P., Weilbaecher, K. N. Dissection of platelet and myeloid cell defects by conditional targeting of the beta 3-integrin subunit. FASEB J. 24, 1117-1127 (2010). www.fasebj.org