Abstract
To evaluate the role of plasminogen activator inhibitor (PAI)-1, a key negative regulator of the plasmin system of extracellular matrix proteases in developmental bone growth and fracture repair, the bone phenotype of male adult PAI-1-deficient mice was determined and femoral fracture healing was compared with that of age- and sex-matched wild-type C57BL/6J control mice. Regarding bone phenotype, the length and size (but not cortical thickness) of the femur of male PAI-1-deficient mice were smaller than those of wild-type controls. Although the total bone mineral content of PAI-1-deficient mice was not significantly different from that of wild-type mice, the total bone area in PAI-1-deficient mice was smaller, leading to an increase in total bone mineral density. With respect to fracture healing, PAI-1-deficient mice developed fracture calluses that were larger and more mineralized than those of wild-type mice but only at 14 days postfracture. These changes were even greater given the smaller size of the normal femur in PAI-1-deficient mice. Surprisingly, the larger fracture callus remodeled rapidly to normal size and mineral content by 21 days postfracture. Examination of fracture histology revealed that these changes were associated with a dramatic increase followed by a rapid remodeling of the fracture callus cartilage. The remodeling of fracture callus cartilage in PAI-1-deficient mice also displayed an abnormal pattern. These findings demonstrate for the first time that PAI-1 (and potentially the plasminogen extracellular matrix protease system) is an important regulator of bone size during developmental growth and plays a regulatory role in the determination of fracture callus size, cartilage formation, and resorption during bone fracture repair.
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Acknowledgement
This work was supported by the U.S. Army Medical Research Acquisition Activity Assistance Award (DAMD17-03-2-0021). The U.S. Army Medical Research Acquisition Activity (820 Chandler Street, Fort Detrick, MD 21702-5014) is the awarding and administering acquisition office. The information contained in this publication does not necessarily reflect the position or the policy of the government, and no official endorsement should be inferred. We are grateful to Emile Davis, Nancy Lowen, Ryan Porte, and Jann Smallwood for technical assistance. All work was performed in facilities provided by the Department of Veterans Affairs.
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Rundle, C.H., Wang, X., Wergedal, J.E. et al. Fracture Healing in Mice Deficient in Plasminogen Activator Inhibitor-1. Calcif Tissue Int 83, 276–284 (2008). https://doi.org/10.1007/s00223-008-9169-7
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DOI: https://doi.org/10.1007/s00223-008-9169-7