The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFβ1 in prostate cells:: Relevance to the accumulation of versican

BACKGROUND. Benign prostatic hyperplasia (BPH) is characterized by a proportional increase in the size of the stromal compartment of the gland, involving alterations to extracellular matrix (ECM) components. Some of these changes have been associated with the activity and expression of transforming growth factor betal (TGF beta 1). Versican (chondroitin sulphate proteoglycan-2) is overexpressed in BPH and prostate cancer and potentially contributes to disease pathology. A sub-group of the ADAMTS lineage of metalloproteases possess versican-degrading properties and are potential regulators of proteoglycan accumulation associated with BPH. These enzymes have one major inhibitor in the ECM, tissue inhibitor of metalloproteinases (TIMP)-3. METHODS. The effect of TGF beta on mRNA expression in prostatic stromal cells was determined by real-time qRT-PCR using primers to ADAMTS-1, -4,-5,-9,-15, versican, and TIMP-3. MMP-inhibitory potential (TIMP activity) of conditioned medium was measured using a fluorometric peptide substrate. RESULTS. Prostatic stromal cell cultures consistently expressed ADAMTS-1, -4,-5,-9,-15 and TIMP-3, in contrast to PC3, DU145, and LNCaP cells which failed to express at least two ADAMTS transcripts. In stromal cells, TGF beta 1 decreased ADAMTS-1, -5,-9, and -15 transcripts and increased ADAMTS-4, versican, and TIMP-3. TGF beta also increased TIMP activity in conditioned medium. CONCLUSIONS. The induction of versican expression by TGF Beta in BPH stromal cells is in agreement with histological studies. The negative effect of TGF beta 1 on ADAMTS-1,-5,-9, and -15 coupled with increases in their inhibitor, TIMP-3 may aid the accumulation of versican in the stromal compartment of the prostate in BPH and prostate cancer. (c) 2004 Wiley-Liss, Inc.