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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1969-1978
PHAGOCYTES
Pathologic gene expression in Gaucher disease:
up-regulation of cysteine proteinases including osteoclastic
cathepsin K
Mary Teresa Moran,
J.
Paul Schofield,
Alison R. Hayman,
Guo-Ping Shi,
Elisabeth Young, and
Timothy M. Cox
From the Department of Medicine, University of
Cambridge, Addenbrooke's Hospital, Cambridge, England; Pulmonary and
Critical Care Medicine, Harvard Medical School, Brigham and Women's
Hospital, Boston, MA; and Chemical Pathology, Great Ormond Street
Hospital NHS Trust, London, England.
Deficiency of lysosomal acid  -glucosidase induces glycolipid
storage in the macrophages of Gaucher disease but the pathways of
multisystem tissue injury and destruction are unknown. To investigate the cognate molecular pathology of this inflammatory disorder, genes
that were differentially expressed in spleen samples from a patient
with Gaucher disease (Gaucher spleen) were isolated. Of 64 complementary DNA (cDNA) fragments sequenced from an enriched Gaucher
cDNA library, 5 encode lysosomal proteins (cathepsins B, K, and
S,  -fucosidase, and acid lipase), 10 encode other known proteins,
and 2 represent novel sequences from human macrophage cell lines.
Transcript abundance of the cathepsins, novel genes, pulmonary and
activation-regulated chemokine (PARC), and NMB, a
putative tumor suppressor gene, was greatly increased. Immunoblotting showed increased mature forms of all 3 cathepsins found in samples of
Gaucher spleens. Immunofluorescence microscopy showed strong cathepsin
B and K reactions in sinusoidal endothelium and Gaucher cells.
The respective means, plus or minus SD, of cathepsin B, K, and
S activities were 183 ± 35, 97 ± 39, and 91 ± 45 nmol/min/mg protein in 4 Gaucher spleens, and 26 ± 4, 10.5 ± 2, and
4.0 ± 2.1 nmol/min/mg protein in 3 control spleens. Plasma cathepsin B, K, and S activities were also elevated in Gaucher disease plasma (P < .001), but compared with control plasma samples,
neither cathepsin B nor K activities were significantly elevated in 8 patients with nonglycosphingolipid lysosomal storage diseases or
in 9 patients with other glycosphingolipidoses, which suggests disease
specificity. All 3 cathepsin activities were increased 2-fold to 3-fold
in Gaucher sera compared with control sera. In all 6 patients treated
by enzyme replacement for 16-22 months, serum cathepsin activities
decreased significantly (P < .01). Longitudinal studies
confirmed the progressive reduction of proteinase activities during
imiglucerase therapy but in 3 Gaucher patients with mild disease not so
treated, serum cathepsin activities remained constant or increased
during follow-up. Enhanced expression of cysteine proteinases may
promote tissue destruction. Moreover, the first identification of
aberrant cathepsin K expression in hematopoietic tissue other than
osteoclasts implicates this protease in the breakdown of the matrix
that characterizes lytic bone lesions in Gaucher disease.
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