Newly generated heparanase knock-out mice unravel co-regulation of heparanase and matrix metalloproteinases.
BACKGROUND
Heparanase, a mammalian endo-beta-D-glucuronidase, specifically degrades heparan sulfate proteoglycans ubiquitously associated with the cell surface and extracellular matrix. This single gene encoded enzyme is over-expressed in most human cancers, promoting tumor metastasis and angiogenesis.


RESULTS
We report that targeted disruption of the murine heparanase gene eliminated heparanase enzymatic activity, resulting in accumulation of long heparan sulfate chains. Unexpectedly, the heparanase knockout (Hpse-KO) mice were fertile, exhibited a normal life span and did not show prominent pathological alterations. The lack of major abnormalities is attributed to a marked elevation in the expression of matrix metalloproteinases, for example, MMP2 and MMP14 in the Hpse-KO liver and kidney. Co-regulation of heparanase and MMPs was also noted by a marked decrease in MMP (primarily MMP-2,-9 and 14) expression following transfection and over-expression of the heparanase gene in cultured human mammary carcinoma (MDA-MB-231) cells. Immunostaining (kidney tissue) and chromatin immunoprecipitation (ChIP) analysis (Hpse-KO mouse embryonic fibroblasts) suggest that the newly discovered co-regulation of heparanase and MMPs is mediated by stabilization and transcriptional activity of beta-catenin.


CONCLUSIONS
The lack of heparanase expression and activity was accompanied by alterations in the expression level of MMP family members, primarily MMP-2 and MMP-14. It is conceivable that MMP-2 and MMP-14, which exert some of the effects elicited by heparanase (i.e., over branching of mammary glands, enhanced angiogenic response) can compensate for its absence, in spite of their different enzymatic substrate. Generation of viable Hpse-KO mice lacking significant abnormalities may provide a promising indication for the use of heparanase as a target for drug development.
Zcharia
Eyal
E
Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Jia
Juan
J
Zhang
Xiao
X
Baraz
Lea
L
Lindahl
Ulf
U
Peretz
Tamar
T
Vlodavsky
Israel
I
Li
Jin-Ping
JP
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005966:Glucuronidase / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D000099175:Heparanase
D005966:Glucuronidase; D020782:Matrix Metalloproteinases; D012333:RNA, Messenger; D000099175:Heparanase