Yuasa Masato, Mignemi Nicholas A, Nyman Jeffry S, Duvall Craig L, Schwartz Herbert S, Okawa Atsushi, Yoshii Toshitaka, Bhattacharjee Gourab, Zhao Chenguang, Bible Jesse E, Obremskey William T, Flick Matthew J, Degen Jay L, Barnett Joey V, Cates Justin M M, Schoenecker Jonathan G
J Clin Invest. 2015 Aug 3;125(8):3117-31. doi: 10.1172/JCI80313. Epub 2015 Jul 27.
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.
骨折修复过程中的骨形成不可避免地始于富含纤维蛋白的基质的血管外沉积物内部或周围。除了在止血中起核心作用外，纤维蛋白还被认为通过支持炎症细胞和间充质祖细胞进入损伤区域来促进骨修复。然而，鉴于有效的纤维蛋白清除失败会阻碍正常伤口修复，纤维蛋白对骨折修复的确切作用，无论是支持性还是有害性，尚不清楚。在这里，我们使用了在纤维蛋白前体纤维蛋白原和纤维蛋白降解酶原方面存在基因和药理学缺陷的小鼠，以探讨纤维蛋白对骨折修复起始至关重要，但纤维蛋白清除受损会导致骨折修复紊乱的假设。与我们的假设相反，纤维蛋白对于长骨骨折修复完全是可有可无的，因为纤维蛋白原缺陷小鼠中的愈合骨折与对照动物中的骨折没有区别。然而，在纤溶酶原缺陷小鼠中未能从骨折部位清除纤维蛋白会严重损害骨折血管化，阻止骨愈合，并导致强烈的异位骨化。在纤溶酶原缺陷动物中进行药理学纤维蛋白原消耗可恢复正常的骨折修复模式，并大大限制异位骨化。因此，纤维蛋白对于骨折修复不是必需的，但纤维蛋白溶解效率低下会减少软骨内血管生成和骨化，从而抑制骨折修复。
