Institut de Recherche Biomédicale des Armées, 92140, Clamart, France.
INSERM UMR-MD-1197, 92140, Clamart, France.
Commun Biol. 2023 Sep 12;6(1):932. doi: 10.1038/s42003-023-05316-w.
Neurogenic heterotopic ossifications are intramuscular bone formations developing following central nervous system injury. The pathophysiology is poorly understood and current treatments for this debilitating condition remain unsatisfying. Here we explored the role of miRNAs in a clinically relevant mouse model that combines muscle and spinal cord injury, and in patients' cells. We found an osteo-suppressive miRNAs response in injured muscle that was hindered when the spinal cord injury was associated. In isolated fibro-adipogenic progenitors from damaged muscle (cells at the origin of ossification), spinal cord injury induced a downregulation of osteo-suppressive miRNAs while osteogenic markers were overexpressed. The overexpression of selected miRNAs in patient's fibro-adipogenic progenitors inhibited mineralization and osteo-chondrogenic markers in vitro. Altogether, we highlighted an osteo-suppressive mechanism involving multiple miRNAs in response to muscle injury that prevents osteogenic commitment which is ablated by the neurologic lesion in heterotopic ossification pathogenesis. This provides new research hypotheses for preventive treatments.
神经源性异位骨化是中枢神经系统损伤后形成的肌肉内骨形成。其病理生理学尚未完全了解，目前针对这种使人衰弱的疾病的治疗仍不尽如人意。在这里，我们在一种临床相关的小鼠模型中探索了 miRNAs 的作用，该模型结合了肌肉和脊髓损伤，并在患者的细胞中进行了研究。我们发现，受伤肌肉中的 miRNA 表现出一种抑制成骨的反应，而当与脊髓损伤相关联时，这种反应受到阻碍。在源自骨化的损伤肌肉的纤维脂肪祖细胞（成骨的起源细胞）中，脊髓损伤诱导了抑制成骨的 miRNA 的下调，同时骨生成标志物过度表达。在患者的纤维脂肪祖细胞中过表达选定的 miRNA 可抑制体外矿化和骨软骨形成标志物。总之，我们强调了一种涉及多种 miRNA 的抑制成骨机制，这种机制对肌肉损伤作出反应，防止成骨细胞的分化，而在异位骨化发病机制中，神经损伤消除了这种分化。这为预防治疗提供了新的研究假设。
