Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle
Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle
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DOI：
10.1002/path.4519
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发表时间：
2015-06-01
影响因子：
7.3
通讯作者：
Levesque, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Genet, Francois;Kulina, Irina;Levesque, Jean-Pierre
神经性异位骨化（NHO）是由于脊髓或创伤性脑损伤导致软组织中骨的异常形成。NHO导致疼痛、强直、血管和神经压迫，并延迟这一高发病率患者组的康复。导致NHO的病理机制仍然未知，因此没有预防或减少NHO的治疗选择。存在罕见遗传形式的异位骨化（HO）的转基因小鼠模型，但其与NHO的相关性值得怀疑。因此，我们在基因未修饰的小鼠中开发了第一个脊髓损伤（SCI）诱导的NHO模型。通过显微计算机断层扫描测量，NHO的形成需要SCI和局部肌肉炎症的结合。我们的NHO模型忠实地再现了SCI患者NHO的许多临床特征，人和小鼠NHO组织中都含有巨噬细胞。肌源性间充质祖细胞在体外对来自NHO小鼠的血清进行成骨细胞分化，而没有额外的外源性成骨刺激。P物质被确定为候选的NHO全身神经肽，因为它在NHO患者的血清中显着升高。然而，在我们的NHO模型中，P物质受体的拮抗作用仅适度减少NHO的体积。相比之下，用氯膦酸盐负载的脂质体消融吞噬巨噬细胞使NHO的大小减少了90%，支持NHO高度依赖于软组织中的炎症和吞噬巨噬细胞的结论。总的来说，我们已经开发了第一个临床相关的NHO模型，并证明了神经损伤和软组织炎症的联合损伤驱动NHO病理生理学。版权所有（c）2015大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Neurological heterotopic ossification (NHO) is the abnormal formation of bone in soft tissues as a consequence of spinal cord or traumatic brain injury. NHO causes pain, ankyloses, vascular and nerve compression and delays rehabilitation in this high-morbidity patient group. The pathological mechanisms leading to NHO remain unknown and consequently there are no therapeutic options to prevent or reduce NHO. Genetically modified mouse models of rare genetic forms of heterotopic ossification (HO) exist, but their relevance to NHO is questionable. Consequently, we developed the first model of spinal cord injury (SCI)-induced NHO in genetically unmodified mice. Formation of NHO, measured by micro-computed tomography, required the combination of both SCI and localized muscular inflammation. Our NHO model faithfully reproduced many clinical features of NHO in SCI patients and both human and mouse NHO tissues contained macrophages. Muscle-derived mesenchymal progenitors underwent osteoblast differentiation in vitro in response to serum from NHO mice without additional exogenous osteogenic stimuli. Substance P was identified as a candidate NHO systemic neuropeptide, as it was significantly elevated in the serum of NHO patients. However, antagonism of substance P receptor in our NHO model only modestly reduced the volume of NHO. In contrast, ablation of phagocytic macrophages with clodronate-loaded liposomes reduced the size of NHO by 90%, supporting the conclusion that NHO is highly dependent on inflammation and phagocytic macrophages in soft tissues. Overall, we have developed the first clinically relevant model of NHO and demonstrated that a combined insult of neurological injury and soft tissue inflammation drives NHO pathophysiology. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.