REGULATION OF INTERSTITIAL COLLAGENASE EXPRESSION AND COLLAGEN DEGRADATION BY RETINOIC ACID IN BONE-CELLS

In osteoblasts, retinoic acid (RA) modulates the synthesis of various proteins, including collagen. However, little is known about the effects of RA on the regulation of interstitial collagenase synthesis and collagen degradation. After treatment of primary osteoblast-enriched (Ob cells from fetal rat calvariae with 100 nM all-trans-RA (tRA), collagenase mRNA levels, as determined by Northern blotting, did not change after 2 h, increased by 13- to 18-fold after 6 h, and remained elevated until 48 h. Exposure of Ob cells to 10 nM to 1 mu M tRA, 13-cis-RA, and 9-cis-RA induced collagenase mRNA in a dose-dependent manner. Collagenase mRNA induction by RA was blocked by cycloheximide. RA increased the stability of collagenase mRNA in Ob cells, suggesting posttranscriptional regulation. Exposure of Ob cells to RA induced immunoreactive procollagenase in medium, as determined by enzyme-linked immunosorbent assay and Western blotting. RA action on collagen degradation was examined in [H-3]proline-pulsed intact calvariae chased with and without tRA for 72 h, The release of [H-3]hydroxyproline into culture medium was increased by 64% in the presence of 10 nM to 1 mu M tRA. In conclusion, RA increases collagenase synthesis and collagen degradation in bone and is likely to play an important role in bone remodeling.