Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic cathepsin K

Deficiency of lysosomal acid beta-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 pa thology of this inflammatory disorder, genes that were differentially expre ssed 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, alpha-fucosidase, and acid lipase), 10 encode other known proteins , and 2 represent novel sequences from human macrophage cell lines. Transcr ipt abundance of the cathepsins, novel genes, pulmonary and activation-regu lated chemokine (PARC), and NMB, a putative tumor suppressor gene, was grea tly increased. Immunoblotting showed increased mature forms of all 3 cathep sins found in samples of Gaucher spleens. Immunofluorescence microscopy sho wed strong cathepsin B and K reactions in sinusoidal endothelium and Gauche r cells. The respective means, plus or minus SD, of cathepsin B, K, and S a ctivities 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 pr otein in 3 control spleens. Plasma cathepsin B, K, and S activities were al so elevated in Gaucher disease plasma (P < .001), but compared with control plasma samples, neither cathepsin B nor K activities were significantly el evated in 8 patients with non-glycosphingolipid lysosomal storage diseases or in 9 patients with other glycosphingolipidoses, which suggests disease s pecificity. All 3 cathepsin activities were increased 2-fold to 3-fold in G aucher sera compared with control sera. In all 6 patients treated by enzyme replacement for 16-22 months, serum cathepsin activities decreased signifi cantly (P < .01), Longitudinal studies confirmed the progressive reduction of proteinase activities during imiglucerase therapy but in 3 Gaucher patie nts with mild disease not so treated, serum cathepsin activities remained c onstant or increased during follow-up. Enhanced expression of cysteine prot einases may promote tissue destruction. Moreover, the first identification of aberrant cathepsin K expression in hematopoietic tissue other than osteo clasts implicates this protease in the breakdown of the matrix that charact erizes lytic bone lesions in Gaucher disease. (C) 2000 by The American Society of Hematology.