Kuehn Sonja C, Koehne Till, Cornils Kerstin, Markmann Sandra, Riedel Christoph, Pestka Jan M, Schweizer Michaela, Baldauf Christina, Yorgan Timur A, Krause Matthias, Keller Johannes, Neven Mona, Breyer Sandra, Stuecker Ralf, Muschol Nicole, Busse Bjoern, Braulke Thomas, Fehse Boris, Amling Michael, Schinke Thorsten
Department of Osteology and Biomechanics.
Department of Osteology and Biomechanics, Department of Orthodontics.
Hum Mol Genet. 2015 Dec 15;24(24):7075-86. doi: 10.1093/hmg/ddv407. Epub 2015 Oct 1.
Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.
黏多糖贮积症 I 型（MPS-I）是一种溶酶体贮积病（LSD），由编码糖胺聚糖降解酶α-L-艾杜糖醛酸酶的IDUA基因失活突变引起。尽管MPS-I与骨骼异常有关，但IDUA缺乏对骨重塑的影响尚不清楚。在此，我们报告Idua基因缺陷小鼠逐渐发展出高骨量表型，成骨细胞谱系细胞中存在病理性溶酶体贮积。组织形态计量学定量分析显示骨形成单位缩短，每骨表面破骨细胞数量减少。这种表型不能通过骨髓移植（BMT）转移到野生型小鼠中。相反，来自野生型供体的BMT可预防Idua基因缺陷小鼠的高骨量表型。在细胞水平上，BMT不仅使Idua基因缺陷的成骨细胞和骨细胞的缺陷正常化，还额外导致破骨细胞生成增加。基于对一名接受过BMT和酶替代疗法（ERT）的MPS-I患者的临床观察，我们对Idua基因缺陷小鼠进行了相应治疗，发现两种治疗方法联合使用可使骨重塑的所有组织形态计量学参数正常化。我们的结果表明，BMT和ERT对Idua基因缺陷小鼠的骨骼重塑有深远影响，因此建议对MPS-I患者在治疗前后监测其骨重塑状态，以避免长期骨骼并发症。
