Abstract

Purpose

MacCune–Albright syndrome (MAS) is a rare autosomal dominant osteo-hormonal disorder. MAS is characterized by a severe form of polyostotic fibrous dysplasia, ‘café-au-lait’ pigmentation of the skin and multiple endocrinopathies. MAS was shown to be caused by mosaic missense somatic mutations in the GNAS gene coding for the alpha-subunit of the stimulatory G-protein. MAS is also associated with radiation-induced malignant tumors, like osteosarcoma, fibrosarcoma and chondrosarcoma but their origin remains misunderstood. In parallel, bisphosphonates treatment was shown to improve the MAS patients’ outcome, notably by increasing bone density but, again, the molecular mechanisms supporting these observations remain misunderstood.

Materials and methods

Here, by using fibroblast and osteoblast cell lines derived from 2 MAS patients, the major radiobiological features of MAS were investigated. Notably, the clonogenic cell survival, the micronuclei and the γH2AX, pATM and MRE11 immunofluorescence assays were applied to MAS cells.

Results

It appears that cells from the 2 MAS patients are associated with a moderate but significant radiosensitivity, a delayed radiation-induced nucleoshuttling of the ATM kinase likely caused by its sequestration in cytoplasm, suggesting impaired DNA double-strand breaks (DSB) repair and signaling in both fibroblasts and osteoblasts. Such delay may be partially corrected by using bisphosphonates combined with statins, which renders cells more radioresistant.

Conclusions

Our findings represent the first radiobiological characterization of fibroblasts and osteoblasts providing from MAS patients. Although the number of studied cases is reduced, our findings suggest that the MAS cells tested belong to the group of syndromes associated with moderate but significant radiosensitivity. Further investigations are however required to secure the clinical transfer of the combination of bisphosphonates and statins, to reduce the disease progression and to better evaluate the potential risks linked to radiation exposure.

中文翻译：

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McCune-Albright 综合征的首次放射生物学特征：ATM 蛋白的影响和他汀类药物 + 双膦酸盐治疗的效果

摘要

目的

MacCune-Albright 综合征 (MAS) 是一种罕见的常染色体显性遗传性骨激素疾病。MAS 的特征是严重的多骨性纤维发育不良、皮肤的“咖啡馆”色素沉着和多种内分泌疾病。MAS 是由编码刺激性 G 蛋白 α 亚基的GNAS基因中的镶嵌错义体细胞突变引起的。MAS 还与放射诱发的恶性肿瘤有关，如骨肉瘤、纤维肉瘤和软骨肉瘤，但它们的起源仍被误解。同时，双膦酸盐治疗被证明可以改善 MAS 患者的预后，特别是通过增加骨密度，但同样，支持这些观察结果的分子机制仍然被误解。

材料和方法

在这里，通过使用来自 2 名 MAS 患者的成纤维细胞和成骨细胞系，研究了 MAS 的主要放射生物学特征。值得注意的是，克隆形成细胞存活、微核和 γH2AX、pATM 和 MRE11 免疫荧光测定应用于 MAS 细胞。

结果

来自 2 名 MAS 患者的细胞似乎与中等但显着的放射敏感性有关，ATM 激酶的延迟辐射诱导的核穿梭可能是由于其在细胞质中的隔离引起的，这表明 DNA 双链断裂 (DSB) 修复和信号传导受损成纤维细胞和成骨细胞。这种延迟可以通过使用双膦酸盐与他汀类药物组合来部分纠正，这使细胞具有更强的抗辐射性。

结论

我们的发现代表了 MAS 患者提供的成纤维细胞和成骨细胞的首次放射生物学特征。尽管研究的病例数减少了，但我们的研究结果表明，测试的 MAS 细胞属于与中等但显着的放射敏感性相关的综合征组。然而，需要进一步的研究以确保双膦酸盐和他汀类药物组合的临床转移，以减少疾病进展并更好地评估与辐射暴露相关的潜在风险。