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Enzyme replacement therapy in mice lacking arylsulfatase B targets bone-remodeling cells, but not chondrocytes
Gretl Hendrickx1, Tatyana Danyukova1, Anke Baranowsky1
1Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Abstract:
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.
Insights
Enzyme replacement therapy (ERT) corrects bone defects in Mucopolysaccharidosis type VI (MPS-VI) by delivering arylsulfatase B (ARSB). However, ERT is less effective for chondrocytes due to their limited uptake of ARSB.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Mucopolysaccharidosis type VI (MPS-VI) is a lysosomal storage disorder caused by arylsulfatase B (Arsb) deficiency.
- Arsb deficiency leads to skeletal abnormalities, including high trabecular bone mass and impaired growth in mice.
Purpose of the Study:
- To investigate the efficacy of enzyme replacement therapy (ERT) using recombinant human ARSB (rhARSB) in Arsb-deficient mice.
- To analyze the impact of ERT on skeletal growth and bone remodeling in MPS-VI.
- To understand the cellular mechanisms underlying ERT effectiveness and limitations in MPS-VI.
Main Methods:
- Treatment of Arsb-deficient mice with weekly injections of rhARSB.
- Histological analysis of femoral heads from ERT-treated MPS-VI patients.
- Comparative analysis of rhARSB endocytosis and mannose receptor expression in different cell types.
- Development of a method to quantify chondroitin sulfation for treatment monitoring.
Main Results:
- ERT prevented bone remodeling abnormalities in Arsb-deficient mice.
- Chondrocyte defects persisted despite ERT, indicating limited therapeutic impact on these cells.
- Histological findings in an ERT-treated MPS-VI patient corroborated that chondrocytes remained pathologically affected.
- Chondrocytes exhibited significantly lower rhARSB endocytosis and reduced mannose receptor expression compared to other cell types.
- A method for quantifying chondroitin sulfation was established for treatment monitoring.
Conclusions:
- Systemically delivered rhARSB is accessible to bone-remodeling cells, effectively correcting skeletal abnormalities in MPS-VI.
- Chondrocytes display inefficient uptake of rhARSB, limiting the therapeutic benefits of ERT for chondrocyte-specific defects in MPS-VI.
- The study highlights the differential cellular uptake of ERT and provides a tool for monitoring treatment efficacy.
