RETINOIC ACID DIRECTLY STIMULATES OSTEOCLASTIC BONE-RESORPTION AND GENE-EXPRESSION OF CATHEPSIN K OC-2/

Vitamin A metabolites such as all-trans-retinoic acid (all-trans-RA) a ffect several steps of metabolic processes in vertebrates. In the last few years, several studies have shown the effect of RA on bone format ion and metabolism. However, mechanisms of its action still remain unc lear, especially with respect to the regulation of bone cells. Therefo re, this study was carried out to clarify how RA regulates the activit y of osteoclasts. Using a pit assay involving unfractionated bone cell s, including osteoclasts obtained from rabbits, we found that RA stimu lated an increase in the bone-resorbing activity in a dose- and time-d ependent manner. Furthermore, this effect occurred more rapidly than t hat of treatments with 1 alpha,25-dihydroxyvitamin D-3. However, this effect of RA may be partly related to cross-talk between osteoclasts a nd other types of cells. Therefore we studied the effect of RA on isol ated osteoclasts. We found that all-trans-RA regulates the gene expres sion of cathepsin K/OC-2, a dominant cysteine proteinase, at the trans criptional level in mature osteoclasts isolated from rabbits. Moreover , retinoic acid-receptor alpha mRNA and retinoid X-receptor beta mRNA were expressed in these mature osteoclasts. Our results indicate that osteoclasts are target cells for RA and that RA might regulate a part of bone formation and metabolism through osteoclasts.