Bone marrow transplantation as a therapy for autosomal dominant osteopetrosis type 2 in mice.
Bone marrow transplantation as a therapy for autosomal dominant osteopetrosis type 2 in mice.
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DOI：
10.1096/fj.202200678r
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发表时间：
2022-09
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常染色体显性骨石化病II型（ADO 2）是一种由氯离子通道7（CLCN 7）基因错义突变引起的骨吸收受损的遗传性骨病。ADO 2的临床特征包括骨折、颌骨骨髓炎、视力丧失，严重者可出现骨髓衰竭。目前，没有针对ADO 2的有效疗法，患者通常接受对症治疗。从理论上讲，骨髓移植（BMT），这是常用的隐性骨硬化症，可用于治疗ADO 2，虽然与BMT相关的并发症的频率是相当高的。我们在129遗传背景上建立了ADO 2敲入（p.G213R突变）小鼠模型，其表型模拟人类ADO 2疾病。为了测试BMT是否可以恢复破骨细胞功能并挽救ADO 2小鼠的骨表型，我们将来自6-8周龄雄性WT供体小鼠的骨髓细胞移植到受体雌性ADO 2小鼠中。此外，为了确定移植时的年龄是否可能在移植成功中发挥作用，我们在年轻（12周龄）和老年（9个月大）ADO 2小鼠中进行了BMT。我们的数据表明，移植WT骨髓的ADO 2小鼠在年轻和年老时在移植后6个月内实现了超过90%的植入。体内DXA数据显示，与ADO 2对照小鼠相比，移植WT骨髓的年轻ADO 2小鼠在移植后6个月具有显著较低的全身和脊柱区域骨矿物质密度（aBMD）。与年龄匹配的对照小鼠相比，老年ADO 2小鼠在移植后4个月和5个月也显示出显著较低的全身、股骨和脊柱aBMD。体内micro-CT数据显示，移植WT骨髓的ADO 2实验小鼠在移植后2个月和4个月时的BV/TV显著低于年轻时的ADO 2对照小鼠。相比之下，ADO 2对照和实验小鼠在老年时的所有移植后时间点显示出相似的BV/TV值。此外，与ADO 2对照小鼠相比，年轻和老年ADO 2实验小鼠在移植后2个月的血清CTX显著更高。与ADO 2对照小鼠相比，年轻ADO 2实验小鼠的血清P1 NP水平在基线和移植后2个月显著更高。这些数据表明，BMT至少可以在年轻和成年时提供一些有益的效果。
Autosomal dominant osteopetrosis type II (ADO2) is a heritable bone disease of impaired osteoclastic bone resorption caused by missense mutations in the chloride channel 7 (CLCN7) gene. Clinical features of ADO2 include fractures, osteomyelitis of jaw, vision loss, and in severe cases, bone marrow failure. Currently, there is no effective therapy for ADO2, and patients usually receive symptomatic treatments. Theoretically, bone marrow transplantation (BMT), which is commonly used in recessive osteopetrosis, could be used to treat ADO2, although the frequency of complications related to BMT is quite high. We created an ADO2 knock-in (p.G213R mutation) mouse model on the 129 genetic background, and their phenotypes mimic the human disease of ADO2. To test whether BMT could restore osteoclast function and rescue the bone phenotypes in ADO2 mice, we transplanted bone marrow cells from 6-8 weeks old male WT donor mice into recipient female ADO2 mice. Also, to determine whether age at the time of transplant may play a role in transplant success, we performed BMT in young (12-week-old) and old (9-month-old) ADO2 mice. Our data indicate that ADO2 mice transplanted with WT marrow achieved more than 90% engraftment up to 6 months post-transplantation at both young and old ages. The in-vivo DXA data revealed that young ADO2 mice transplanted with WT marrow had significantly lower whole body and spine areal bone mineral density (aBMD) at month 6 post-transplantation compared to the ADO2 control mice. The old ADO2 mice also displayed significantly lower whole body, femur and spine aBMD at months 4 and 5 post-transplantation compared to the age-matched control mice. The in-vivo micro-CT data showed that ADO2 experimental mice transplanted with WT marrow had significantly lower BV/TV at months 2 and 4 post-transplantation compared to the ADO2 control mice at young age. In contrast, ADO2 control and experimental mice displayed similar BV/TV values for all post-transplantation time points at old age. In addition, serum CTX was significantly higher at month 2 post-transplantation in both young and old ADO2 experimental mice compared to the ADO2 control mice. Serum P1NP levels in young ADO2 experimental mice were significantly higher at baseline and month 2 post-transplantation compared to the ADO2 control mice. These data suggest that BMT may provide, at least, some beneficial effect at both young and adult ages.
影响因子：
4.8
作者：
Martinez C;Polgreen LE;DeFor TE;Kivisto T;Petryk A;Tolar J;Orchard PJ
通讯作者：
Orchard PJ