The Lysosomal Protein Arylsulfatase B Is a Key Enzyme Involved in Skeletal Turnover

Abstract

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. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI—Evidence from in vitro and in vivo models

“…In MPS VI mouse models [30,36,37], consistent with the MPS VI disease physiopathology, an accumulation of total sulphated GAG can be demonstrated in liver and kidney either by Alcian Blue staining, specific for sulphated GAG (S3 Fig), or by measuring total GAG content (Fig 4). The progression of MPS VI phenotype in Arsbmice could be monitored by measuring the accumulation of sulphated GAG in liver and kidney at different time points (1, 3 and 6 months of age) (Fig 4).…”

“…MPS VI model nonsense mutation Arsb m1J homozygous mice [29,30] (referred to as Arsbthroughout the manuscript) and WT littermates were obtained from internal breeding of stock mice derived from The Jackson Laboratory strain No: 005598 (C57BL/6J-Arsb m1J / GrsrJ). Genotyping and Arsb m1J mutation identification were performed according to the protocol provided by The Jackson Laboratory.…”

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

“…Increases in chondroitin sulfate and the chondroitin sulfate proteoglycan versican were identified in more aggressive prostate cancers . Increased C4S has significant consequences for transcription, signaling, metabolism, and proliferation in the prostate and in other tissues …”

Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

“…Other groups are likewise finding that mannose-terminated lysosomal hydrolases exhibit a considerable extent of therapeutic efficacy for Gaucher disease and Niemann-Pick disease [37,38]. Furthermore, mannose-dependent uptake of commercial M6P-tagged arylsulfatase B (Naglazyme ® (BioMarin Pharmaceutical Inc., San Rafael, CA, USA) was shown in primary cultured cells from MPS VI mice [39]. These studies have opened up the possibility that a plant-based platform for generating mannose-terminated enzyme will possess efficacy in ERT regimes, i.e., without the requirement for additional processing to create the M6P motif.…”