ISSN:
0021-9541
Keywords:
Life and Medical Sciences
;
Cell & Developmental Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
,
Medicine
Notes:
Retinoids and transforming growth factor-b̃1 (TGF-b̃1) reduce the transcriptional activation of matrix metalloproteinases (MMPs) and increase the expression of the specific tissue inhibitor of MMPs (TIMP-1) in fibroblasts. In contrast, all-trans-retinoic acid (retinoic acid) increases MMP expression in osteoblasts. Therefore, the mechanistic aspects of TIMP-1 regulation by retinoic acid in primary cultures of rat calvarial bone cell populations were studied and compared with those of TGF-b̃1 to determine if modulation of TIMP-1 would augment MMP expression. Retionic acid was found to reduce TIMP-1 mRNA levels after 24 and 72 hr of culture by up to 60% in a dose-dependent manner. Maximal inhibition occurred at 10-6 M retinoic acid with half maximal repression at ∼5 × 10-8 M. To determine the half life of TIMP-1 mRNA, the specific RNA polymerase II inhibitor DRB was added to cultures and the chase RNA analyzed by slot blots. TIMP-1 mRNA had a half life of ∼14 hr and this was unaltered by retinoic acid treatment, suggesting that retinoic acid exerts its effects on TIMP-1 transcriptionally. When retinoic acid was added to cycloheximide-treated cultures TIMP-1 mRNA levels were reduced at 5 hr compared with controls. This showed that ongoing protein synthesis was not required to mediate the retinoic acid repression of TIMP-1 mRNA levels and supports the evidence that retinoic acid acts at the transcriptional level to reduce TIMP-1 expression. In contrast, TGF-b̃1 increased TIMP-1 mRNA levels by 3.5-fold at 24 hr to〉10-fold at 72 hr without alterations in mRNA stability indicating that transforming growth factor (TGF)-b̃1 also acts at the transcriptional level to upregulate TIMP-1 expression in bone cells. Thus, these studies have revealed that TIMP-1 regulation by retinoic acid is different in osteoblasts from other cells and that retinoic acid has the property of generating resorptive and formative cell phenotypes in a tissue-specific manner. In bone, reduced TIMP-1 expression would favor bone matrix degradation and bone resorption that is a characteristic action of retinoids. © 1995 Wiley-Liss, Inc.
Additional Material:
6 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcp.1041640104
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