Temporary inhibition of the plasminogen activator inhibits periosteal chondrogenesis and promotes periosteal osteogenesis during appendicular bone fracture healing.
Temporary inhibition of the plasminogen activator inhibits periosteal chondrogenesis and promotes periosteal osteogenesis during appendicular bone fracture healing.
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DOI：
10.1016/j.bone.2018.04.016
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发表时间：
2018-07
期刊：
影响因子：
4.1
通讯作者：
Leucht P
中科院分区：
文献类型：
--
作者：
Bravo D;Josephson AM;Bradaschia-Correa V;Wong MZ;Yim NL;Neibart SS;Lee SN;Huo J;Coughlin T;Mizrahi MM;Leucht P
氨基己酸被批准为一种抗纤溶药物，用于关节置换和脊柱融合手术，以限制围手术期失血。以前的动物研究已经证明了氨基己酸在脊柱融合模型中的促成骨作用。在这里，我们测试了氨基己酸是否能促进附件骨愈合，并试图揭示氨基己酸在骨再生过程中对骨祖细胞(OPC)的影响。我们采用了一种成熟的小鼠股骨骨折模型，在成年C57BL/6J小鼠上，在围手术期注射了两次氨基己酸。常规组织学分析、生物力学测试和显微CT分析用于评估骨痂的体积和强度、祖细胞的增殖、分化和体内重塑。两种不同的异位移植模型被用来研究早期骨折血肿内生长因子环境对骨祖细胞命运决定的影响。氨基己酸治疗的股骨骨折愈合后有明显较小的软骨骨痂，在异位移植试验中也观察到了这种影响。我们假设氨基己酸治疗导致早期骨折血肿稳定，导致由早期血肿产生的生长因子环境的改变。基因和蛋白表达分析证实，氨基己酸处理导致WNT和BMP信号增加，转化生长因子-β信号减少，导致这种软骨内成骨模型从软骨向成骨分化转变。这些实验首次证明，在使用氨基己酸的骨折愈合过程中，抑制纤溶酶原激活物导致骨膜成骨前体细胞的细胞命运决定改变，具有成骨分化的优势，导致骨痂更大、更强。这些发现可能为氨基己酸提供一种很有前途的新用途，氨基己酸已经得到FDA的批准，并提供了非常安全的风险概况。
Aminocaproic acid is approved as an anti-fibrinolytic for use in joint replacement and spinal fusion surgeries to limit perioperative blood loss. Previous animal studies have demonstrated a pro-osteogenic effect of aminocaproic acid in spine fusion models. Here, we tested if aminocaproic acid enhances appendicular bone healing and we sought to uncover the effect of aminocaproic acid on osteoprogenitor cells (OPCs) during bone regeneration. We employed a well-established murine femur fracture model in adult C57BL/6J mice after receiving two peri-operative injections of aminocaproic acid. Routine histological assays, biomechanical testing and micro-CT analyses were utilized to assess callus volume, and strength, progenitor cell proliferation, differentiation, and remodeling in vivo. Two disparate ectopic transplantation models were used to study the effect of the growth factor milieu within the early fracture hematoma on osteoprogenitor cell fate decisions. Aminocaproic acid treated femur fractures healed with a significantly smaller cartilaginous callus, and this effect was also observed in the ectopic transplantation assays. We hypothesized that aminocaproic acid treatment resulted in a stabilization of the early fracture hematoma, leading to a change in the growth factor milieu created by the early hematoma. Gene and protein expression analysis confirmed that aminocaproic acid treatment resulted in an increase in Wnt and BMP signaling and a decrease in TGF-β-signaling, resulting in a shift from chondrogenic to osteogenic differentiation in this model of endochondral bone formation. These experiments demonstrate for the first time that inhibition of the plasminogen activator during fracture healing using aminocaproic acid leads to a change in cell fate decision of periosteal osteoprogenitor cells, with a predominance of osteogenic differentiation, resulting in a larger and stronger bony callus. These findings may offer a promising new use of aminocaproic acid, which is already FDA-approved and offers a very safe risk profile.
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DOI：
10.1038/nrrheum.2014.164
发表时间：
2015-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.2
作者：
Daci, E;Everts, V;Carmeliet, G
通讯作者：
Carmeliet, G
影响因子：
4.2
作者：
Rundle, Charles H.;Wang, Xiaoguang;Lau, K. -H. William
通讯作者：
Lau, K. -H. William
影响因子：
3
作者：
Thompson, GH;Florentino-Pineda, I;Poe-Kochert, C
通讯作者：
Poe-Kochert, C
影响因子：
6.2
作者：
Kim, Jae-Beorn;Leucht, Philipp;Helms, Jill A.
通讯作者：
Helms, Jill A.