Repression of tissue inhibitor of matrix metalloproteinase expression by all‐trans‐retinoic acid in rat bone cell populations: Comparison with transforming growth factor‐βT1

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Abstract
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.

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