TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells
TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells
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DOI：
10.1073/pnas.1018501108
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发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Nanchahal, Jagdeep
中科院分区：
文献类型：
--
作者：
Glass, Graeme E.;Chan, James K.;Nanchahal, Jagdeep
随着人口老龄化，骨折的发生率增加，包括正常骨中典型的闭合性骨折和不常见的开放性骨折，以及骨质疏松症患者的脆性骨折。对于年龄较大的人群，迫切需要诱导可预测的骨形成以及改善髋关节置换等情况下的植入物固定。使用小鼠模型的缓慢愈合骨折，我们以前已经表明，覆盖骨折与肌肉加速骨折愈合和增加工会的力量。在这里，我们显示，细胞从肌肉收获后3天暴露于邻近骨折分化成骨细胞，并形成骨结节在体外。这些细胞的成骨潜力超过脂肪和皮肤来源的基质细胞，相当于骨髓基质细胞。人胫骨骨折块培养上清液促进肌源性基质细胞（MDSC）的成骨和迁移。造成这种情况的主要因素是TNF-α，它首先促进MDSC迁移，然后在低浓度下促进成骨分化。然而，TNF-α在高浓度下是抑制性的。在我们的小鼠模型中，在骨折部位添加1 ng/mL的TNF-α加速愈合。这些数据表明，操纵局部炎症环境来募集，然后分化邻近的MDSC，可能是一种简单而有效的方法来增强骨形成和加速骨折修复。我们的研究结果是基于人体标本和体内小鼠模型的组合，因此，可以转化为临床护理。
With an aging population, skeletal fractures are increasing in incidence, including the typical closed and the less common open fractures in normal bone, as well as fragility fractures in patients with osteoporosis. For the older age group, there is an urgent unmet need to induce predictable bone formation as well as improve implant fixation in situations such as hip joint replacement. Using a murine model of slow-healing fractures, we have previously shown that coverage of the fracture with muscle accelerated fracture healing and increased union strength. Here, we show that cells from muscle harvested after 3 d of exposure to an adjacent fracture differentiate into osteoblasts and form bone nodules in vitro. The osteogenic potential of these cells exceeds that of adipose and skin-derived stromal cells and is equivalent to bone marrow stromal cells. Supernatants from human fractured tibial bone fragments promote osteogenesis and migration of muscle-derived stromal cells (MDSC) in vitro. The main factor responsible for this is TNF-alpha, which promotes first MDSC migration, then osteogenic differentiation at low concentrations. However, TNF-alpha is inhibitory at high concentrations. In our murine model, addition of TNF-alpha at 1 ng/mL at the fracture site accelerated healing. These data indicate that manipulating the local inflammatory environment to recruit, then differentiate adjacent MDSC, may be a simple yet effective way to enhance bone formation and accelerate fracture repair. Our findings are based on a combination of human specimens and an in vivo murine model and may, therefore, translate to clinical care.