The Lysosomal Protein Arylsulfatase B Is a Key Enzyme Involved in Skeletal Turnover
The Lysosomal Protein Arylsulfatase B Is a Key Enzyme Involved in Skeletal Turnover
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DOI：
10.1002/jbmr.3563
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发表时间：
2018-12-01
影响因子：
6.2
通讯作者：
Schinke, Thorsten
中科院分区：
文献类型：
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作者：
Pohl, Sandra;Angermann, Alexandra;Schinke, Thorsten
骨骼肌病理常见于溶酶体贮积症，但骨重塑细胞类型中特定溶酶体酶的相关性尚不明确。两种溶酶体酶，即组织蛋白酶K（Ctsk）和Acp 5（也称为抗酒石酸酸性磷酸酶），一直被认为是分化破骨细胞的分子标志蛋白。然而，尽管半胱氨酸蛋白酶Ctsk直接参与骨基质蛋白的降解，但Acp 5在破骨细胞中的分子功能仍然未知。在这里，我们表明，Acp5，与Acp2（溶酶体酸性磷酸酶），是必需的溶酶体甘露糖6-磷酸靶向信号的去磷酸化，以促进特定的溶酶体酶的活性。使用无偏的方法，我们确定了糖胺聚糖降解酶芳基硫酸酯酶B（Arsb），在粘多糖沉积症VI型（MPS-VI）突变，作为破骨细胞标志物，其活性取决于Acp 2和Acp 5的去磷酸化。与Acp2/Acp5（-/-）小鼠相似，Arsb缺陷小鼠显示破骨细胞中的溶酶体蓄积、破骨细胞活性受损和高小梁骨量。值得注意的是，在Arsb缺陷小鼠的骨细胞中观察到最显著的溶酶体蓄积，但这种病理学并不损害硬化蛋白（Sost）和Fgf23的产生。由于酶替代疗法（ERT）对MPS-VI中骨重建的影响尚不清楚，因此我们还通过每周注射重组人ARSB对12至24周龄的ArSB缺陷小鼠进行了治疗。我们发现ArSb缺陷小鼠的高骨量表型和潜在的骨细胞缺陷在小梁区室中被ERT完全纠正。总之，我们的研究结果不仅表明Acp 5在破骨细胞中的功能与溶酶体酶的去磷酸化和活化有关，而且还为ERT纠正溶酶体贮积症中骨细胞病理的可行性提供了重要的原理证明。(c)2018作者骨与矿物质研究杂志由Wiley Periodicals Inc.出版。
Skeletal pathologies are frequently observed in lysosomal storage disorders, yet the relevance of specific lysosomal enzymes in bone remodeling cell types is poorly defined. Two lysosomal enzymes, ie, cathepsin K (Ctsk) and Acp5 (also known as tartrate-resistant acid phosphatase), have long been known as molecular marker proteins of differentiated osteoclasts. However, whereas the cysteine protease Ctsk is directly involved in the degradation of bone matrix proteins, the molecular function of Acp5 in osteoclasts is still unknown. Here we show that Acp5, in concert with Acp2 (lysosomal acid phosphatase), is required for dephosphorylation of the lysosomal mannose 6-phosphate targeting signal to promote the activity of specific lysosomal enzymes. Using an unbiased approach we identified the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), mutated in mucopolysaccharidosis type VI (MPS-VI), as an osteoclast marker, whose activity depends on dephosphorylation by Acp2 and Acp5. Similar to Acp2/Acp5(-/-) mice, Arsb-deficient mice display lysosomal storage accumulation in osteoclasts, impaired osteoclast activity, and high trabecular bone mass. Of note, the most prominent lysosomal storage accumulation was observed in osteocytes from Arsb-deficient mice, yet this pathology did not impair production of sclerostin (Sost) and Fgf23. Because the influence of enzyme replacement therapy (ERT) on bone remodeling in MPS-VI is still unknown, we additionally treated Arsb-deficient mice by weekly injection of recombinant human ARSB from 12 to 24 weeks of age. We found that the high bone mass phenotype of Arsb-deficient mice and the underlying bone cell deficits were fully corrected by ERT in the trabecular compartment. Taken together, our results do not only show that the function of Acp5 in osteoclasts is linked to dephosphorylation and activation of lysosomal enzymes, they also provide an important proof-of-principle for the feasibility of ERT to correct bone cell pathologies in lysosomal storage disorders. (c) 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.