Medicine, Indiana University School of Medicine, IN, USA.
Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA.
J Bone Miner Res. 2015 Nov;30(11):2005-13. doi: 10.1002/jbmr.2545. Epub 2015 May 14.
ADO2 is a heritable osteosclerotic disorder that usually results from heterozygous missense dominant negative mutations in the chloride channel 7 gene (CLCN7). ADO2 is characterized by a wide range of features and severity, including multiple fractures, impaired vision due to secondary bony overgrowth and/or the lack of the optical canal enlargement with growth, and osteonecrosis/osteomyelitis. The disease is presently incurable, although anecdotal evidence suggests that calcitriol and interferon gamma-1b (IFN-G) may have some beneficial effects. To identify the role of these drugs for the treatment of ADO2, we utilized a knock-in (G213R mutation in Clcn7) ADO2 mouse model that resembles the human disease. Six-week-old ADO2 heterozygous mice were administered vehicle (PBS) or calcitriol or IFN-G 5 times per week for 8 weeks. We determined bone phenotypes using DXA and μCT, and analyzed serum biochemistry and bone resorption markers. ADO2 mice treated with all doses of IFN-G significantly (p<0.05) attenuated the increase of whole body aBMD and distal femur BV/TV gain in both male and female compared to the vehicle group. In contrast, mice treated with low and medium doses of calcitriol showed a trend of higher aBMD and BV/TV whereas high dose calcitriol significantly (p<0.05) increased bone mass compared to the vehicle group. The calcium and phosphorus levels did not differ between vehicle and IFN-G or calcitriol treated mice; however, we detected significantly (p<0.05) elevated levels of CTX/TRAP5b ratio in IFN-G treated mice. Our findings indicate that while IFN-G at all doses substantially improved the osteopetrotic phenotypes in ADO2 heterozygous mice, calcitriol treatment at any dose did not improve the phenotype and at high dose further increased bone mass. Thus, use of high dose calcitriol therapy in ADO2 patients merits serious reconsideration. Importantly, our data support the prospect of a clinical trial of IFN-G in ADO2 patients.
ADO2 是一种遗传性骨质硬化疾病，通常由氯离子通道 7 基因（CLCN7）的杂合错义显性负突变引起。ADO2 的特征是具有广泛的特征和严重程度，包括多发性骨折、由于二次骨过度生长和/或生长过程中视神经管扩大不足而导致的视力受损，以及骨坏死/骨髓炎。该疾病目前无法治愈，尽管有传闻证据表明，骨化三醇和干扰素 γ-1b（IFN-G）可能具有一些有益的作用。为了确定这些药物治疗 ADO2 的作用，我们利用了一种类似于人类疾病的 Clcn7 基因中的 G213R 突变的敲入（knock-in）ADO2 小鼠模型。6 周龄的 ADO2 杂合子小鼠每周接受 5 次载体（PBS）或骨化三醇或 IFN-G 治疗，持续 8 周。我们使用 DXA 和 μCT 来确定骨骼表型，并分析血清生化和骨吸收标志物。与载体组相比，所有剂量的 IFN-G 治疗的 ADO2 小鼠的全身 aBMD 和远端股骨 BV/TV 增益均显著（p<0.05）降低。相比之下，低剂量和中剂量的骨化三醇治疗的小鼠表现出更高的 aBMD 和 BV/TV 的趋势，而高剂量的骨化三醇与载体组相比显著（p<0.05）增加了骨量。载体和 IFN-G 或骨化三醇治疗的小鼠之间的钙和磷水平没有差异；然而，我们检测到 IFN-G 治疗的小鼠的 CTX/TRAP5b 比值显著（p<0.05）升高。我们的研究结果表明，虽然所有剂量的 IFN-G 都显著改善了 ADO2 杂合子小鼠的骨质硬化表型，但任何剂量的骨化三醇治疗都没有改善表型，而高剂量则进一步增加了骨量。因此，在 ADO2 患者中使用高剂量的骨化三醇治疗需要认真考虑。重要的是，我们的数据支持在 ADO2 患者中进行 IFN-G 临床试验的前景。
