title: Fracture healing in mice deficient in plasminogen activator inhibitor-1.
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.
authors.affiliation: Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Administration Medical Center, 11201 Benton Street, Loma Linda, CA 92357, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Rundle
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Wang
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
authors.forename: K-H William
authors.initials: KH
authors.lastname: Lau
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology; D004195:Disease Models, Animal; D005269:Femur / Q000166:cytology / Q000502:physiology; D017102:Fracture Healing / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D010960:Plasminogen Activators / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator