title: Urokinase plasminogen activator gene deficiency inhibits fracture cartilage remodeling.
abstract: Urokinase plasminogen activator (uPA) regulates a proteolytic cascade of extracellular matrix degradation that functions in tissue development and tissue repair. The development and remodeling of the skeletal extracellular matrix during wound healing suggests that uPA might regulate bone development and repair. To determine whether uPA functions regulate bone development and repair, we examined the basal skeletal phenotype and endochondral bone fracture repair in uPA-deficient mice. The skeletal phenotype of uPA knockout mice was compared with that of control mice under basal conditions by dual-energy X-ray absorptiometry and micro-CT analysis, and during femur fracture repair by micro-CT and histological examination of the fracture callus. No effects of uPA gene deficiency were observed in the basal skeletal phenotype of the whole body or the femur. However, uPA gene deficiency resulted in increased fracture callus cartilage abundance during femur fracture repair at 14 days healing. The increase in cartilage corresponded to reduced tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts in the uPA knockout fracture callus at this time, consistent with impaired osteoclast-mediated remodeling of the fracture cartilage. CD31 staining was reduced in the knockout fracture tissues at this time, suggesting that angiogenesis was also reduced. Osteoclasts also colocalized with CD31 expression in the endothelial cells of the fracture tissues during callus remodeling. These results indicate that uPA promotes remodeling of the fracture cartilage by osteoclasts that are associated with angiogenesis and suggest that uPA promotes angiogenesis and remodeling of the fracture cartilage at this time of bone fracture repair.
authors.affiliation: Musculoskeletal Disease Center, Research Service (151), Jerry L. Pettis Memorial Veterans Administration Medical Center, 11201 Benton Street, Loma Linda, CA, 92357, USA.
authors.forename: Nicoleta L
authors.initials: NL
authors.lastname: Popa
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.forename: K-H William
authors.initials: KH
authors.lastname: Lau
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
authors.forename: Charles H
authors.initials: CH
authors.lastname: Rundle
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology; D017102:Fracture Healing / Q000235:genetics*; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
chemical_list: D014568:Urokinase-Type Plasminogen Activator