Uptake of a Recombinant Human α-L-Iduronidase (laronidase) by Cultured Fibroblasts and Osteoblasts

To examine the uptake of a recombinant human α-L-iduronidase (laronidase) by cultured fibroblasts from a patient with mucopolysaccharidosis I (MPS I) and its effect on the cleavage of accumulated substrates, we performed enzymological, Western blotting, immunocytochemical and morphological studies....

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2008/09/01, Vol.31(9), pp.1691-1695
Main Authors: Tsukimura, Takahiro, Tajima, Youichi, Kawashima, Ikuo, Fukushige, Tomoko, Kanzaki, Tamotsu, Kanekura, Takuro, Ikekita, Masahiko, Sugawara, Kanako, Suzuki, Toshihiro, Togawa, Tadayasu, Sakuraba, Hitoshi
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
enzyme replacement therapy
Fibroblasts - metabolism
Fibroblasts - ultrastructure
Humans
Iduronidase - metabolism
Kinetics
mannose 6-phosphate receptor
Mice
mucopolysaccharidosis I
Mucopolysaccharidosis I - metabolism
osteoblast
Osteoblasts - metabolism
Osteoblasts - ultrastructure
Receptor, IGF Type 2 - metabolism
Recombinant Proteins - metabolism
α-L-iduronidase
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Summary:To examine the uptake of a recombinant human α-L-iduronidase (laronidase) by cultured fibroblasts from a patient with mucopolysaccharidosis I (MPS I) and its effect on the cleavage of accumulated substrates, we performed enzymological, Western blotting, immunocytochemical and morphological studies. Laronidase was incorporated into the MPS I cells dose-dependently mainly via mannose 6-phosphate (M6P) receptors. Then the incorporated enzyme was transported to lysosomes and processed to the mature form, the pathological changes of the cells being improved. Furthermore, we compared the uptake of laronidase by cultured mouse osteoblasts with that by cultured mouse fibroblasts. The enzyme was incorporated into the cultured mouse osteoblasts mainly via M6P receptors, although mannose (Man) receptors were partially involved in the uptake of the enzyme, as in the cultured fibroblasts. But the uptake by the former was apparently lower than that by the latter. The administration of a high dose of the enzyme or development of a recombinant α-L-iduronidase containing many M6P residues is required for further improvement of enzyme replacement therapy for skeletal disorders caused by MPS I.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.31.1691