Enzyme replacement therapy in mice lacking arylsulfatase B targets bone-remodeling cells, but not chondrocytes
Enzyme replacement therapy in mice lacking arylsulfatase B targets bone-remodeling cells, but not chondrocytes
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DOI：
10.1093/hmg/ddaa006
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发表时间：
2020-03-01
影响因子：
3.5
通讯作者：
Schinke, Thorsten
中科院分区：
文献类型：
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作者：
Hendrickx, Gretl;Danyukova, Tatyana;Schinke, Thorsten
粘多糖样沉积症VI型（MPS-VI），由糖胺聚糖降解酶芳基硫酸酯酶B（Arsb）的突变失活引起，是一种主要影响骨骼的溶酶体贮积症。我们以前曾报道过ArSb缺陷小鼠显示高骨小梁骨量和受损的骨骼生长。在本研究中，我们通过每周注射重组人ARSB（rhARSB）来分析酶替代疗法（ERT）对骨骼生长和骨重建的影响。我们发现所有ArSb缺陷小鼠的骨重建异常都能被ERT预防，而软骨细胞缺陷则不能。同样，对ERT治疗的MPS-VI患者手术取出的股骨头进行组织学分析，发现只有软骨细胞受到病理影响。值得注意的是，与其他细胞类型的并排比较表明，软骨细胞内吞rhARSB的能力显著降低，同时甘露糖受体表达低。最后，我们利用ArSb缺陷小鼠来建立用于治疗监测的硫酸软骨素定量。我们的数据表明，骨重塑细胞类型是可访问的全身交付rhARSB，而吸收到软骨细胞是低效的。
Mucopolysaccharidosis type VI (MPS-VI), caused by mutational inactivation of the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), is a lysosomal storage disorder primarily affecting the skeleton. We have previously reported that Arsb-deficient mice display high trabecular bone mass and impaired skeletal growth. In the present study, we treated them by weekly injection of recombinant human ARSB (rhARSB) to analyze the impact of enzyme replacement therapy (ERT) on skeletal growth and bone remodeling. We found that all bone-remodeling abnormalities of Arsb-deficient mice were prevented by ERT, whereas chondrocyte defects were not. Likewise, histologic analysis of the surgically removed femoral head from an ERT-treated MPS-VI patient revealed that only chondrocytes were pathologically affected. Remarkably, a side-by-side comparison with other cell types demonstrated that chondrocytes have substantially reduced capacity to endocytose rhARSB, together with low expression of the mannose receptor. We finally took advantage of Arsb-deficient mice to establish quantification of chondroitin sulfation for treatment monitoring. Our data demonstrate that bone-remodeling cell types are accessible to systemically delivered rhARSB, whereas the uptake into chondrocytes is inefficient.