title: Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification.
abstract: Bone formation during fracture repair inevitably initiates within or around extravascular deposits of a fibrin-rich matrix. In addition to a central role in hemostasis, fibrin is thought to enhance bone repair by supporting inflammatory and mesenchymal progenitor egress into the zone of injury. However, given that a failure of efficient fibrin clearance can impede normal wound repair, the precise contribution of fibrin to bone fracture repair, whether supportive or detrimental, is unknown. Here, we employed mice with genetically and pharmacologically imposed deficits in the fibrin precursor fibrinogen and fibrin-degrading plasminogen to explore the hypothesis that fibrin is vital to the initiation of fracture repair, but impaired fibrin clearance results in derangements in bone fracture repair. In contrast to our hypothesis, fibrin was entirely dispensable for long-bone fracture repair, as healing fractures in fibrinogen-deficient mice were indistinguishable from those in control animals. However, failure to clear fibrin from the fracture site in plasminogen-deficient mice severely impaired fracture vascularization, precluded bone union, and resulted in robust heterotopic ossification. Pharmacological fibrinogen depletion in plasminogen-deficient animals restored a normal pattern of fracture repair and substantially limited heterotopic ossification. Fibrin is therefore not essential for fracture repair, but inefficient fibrinolysis decreases endochondral angiogenesis and ossification, thereby inhibiting fracture repair.
authors.forename: Masato
authors.initials: M
authors.lastname: Yuasa
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Mignemi
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.forename: Craig L
authors.initials: CL
authors.lastname: Duvall
authors.forename: Herbert S
authors.initials: HS
authors.lastname: Schwartz
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yoshii
authors.forename: Gourab
authors.initials: G
authors.lastname: Bhattacharjee
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhao
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Bible
authors.forename: William T
authors.initials: WT
authors.lastname: Obremskey
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.forename: Justin M M
authors.initials: JM
authors.lastname: Cates
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Schoenecker
mesh_terms: D000818:Animals; D005337:Fibrin / Q000235:genetics / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism; D005342:Fibrinolysis; D017102:Fracture Healing; D051379:Mice; D018345:Mice, Knockout; D009999:Ossification, Heterotopic / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism
chemical_list: D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen