Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification
Masato Yuasa, Nicholas A. Mignemi, Jeffry S. Nyman, Craig L. Duvall, Herbert S. Schwartz, Atsushi Okawa, Toshitaka Yoshii, Gourab Bhattacharjee, Chenguang Zhao, Jesse E. Bible, William T. Obremskey, Matthew J. Flick, Jay L. Degen, Joey V. Barnett, Justin M.M. Cates, Jonathan G. Schoenecker
Masato Yuasa, Nicholas A. Mignemi, Jeffry S. Nyman, Craig L. Duvall, Herbert S. Schwartz, Atsushi Okawa, Toshitaka Yoshii, Gourab Bhattacharjee, Chenguang Zhao, Jesse E. Bible, William T. Obremskey, Matthew J. Flick, Jay L. Degen, Joey V. Barnett, Justin M.M. Cates, Jonathan G. Schoenecker
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Research Article Bone biology Hematology Hepatology Nephrology Pulmonology

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

Masato Yuasa, Nicholas A. Mignemi, Jeffry S. Nyman, Craig L. Duvall, Herbert S. Schwartz, Atsushi Okawa, Toshitaka Yoshii, Gourab Bhattacharjee, Chenguang Zhao, Jesse E. Bible, William T. Obremskey, Matthew J. Flick, Jay L. Degen, Joey V. Barnett, Justin M.M. Cates, Jonathan G. Schoenecker

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Figure 1

Fibrin is essential for limiting hemorrhage, but not for fracture callus formation.

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Fibrin is essential for limiting hemorrhage, but not for fracture callus...
(A) Immunofluorescence-based detection of fibrin (red) at fracture site (yellow arrow) in WT and fibrinogen-deficient (Fbg–/–) mice. Note that fibrin was prominent in WT mice proximal to the fracture site (approximate location of the femora cortical bone outlined with white dotted lines), whereas fibrin was completely absent in Fbg–/– animals at 1 DPF. (B) Gross photographs of WT and Fbg–/– mouse extremities at 1 DPF showing local excessive bleeding and hematoma formation in Fbg–/– mice (outlined by yellow dashes) compared with WT mice. (C) Temporal radiographic analysis of fractured femurs (yellow arrows) in WT and Fbg–/– mice. Note that the formation (blue arrowheads) of the fracture callus and macroscopic hard-tissue callus remodeling (dashed yellow lines) of the fracture callus were effectively indistinguishable in WT and Fbg–/– mice. n ≥ 10 for each genotype. Scale bars: 1 mm.