PARATHYROID HORMONE-INDUCED RESORPTION IN FETAL-RAT LIMB BONES IS ASSOCIATED WITH PRODUCTION OF THE METALLOPROTEINASES COLLAGENASE AND GELATINASE-B

The role of matrix metalloproteinases in parathyroid hormone (PTH)-ind uced bone resorption was assayed using a fetal rat limb bone culture s ystem, Cotreatment of bones with PTH and recombinant inhibitor of meta lloproteinases, TIMP-1, in vitro, inhibited the PTH-stimulated Ca-45 r elease from the limb bones without affecting beta-glucuronidase releas e, TIMP-1 was fully effective when added during only the final 24 h of a 72 h culture with PTH but was ineffective when added for only the f irst 24 h of the 72 h culture, In contrast, calcitonin (CT) was effect ive when added for either the first 24 or the final 24 h of the cultur e, Using in situ hybridization, the mRNA for collagenase was detected in mononuclear cells of cultured bone, Treatment of the bones with PTH resulted in an increase in the number of cells producing collagenase mRNA, some of which had osteoclastic morphology. PTH also caused a dra matic induction of the mRNA for the 92-kD gelatinase B metalloproteina se in both mononuclear and osteoclastic cells, There was no detectable mRNA for the metalloproteinases stromelysin-1, stromelysin-2, or matr ilysin in PTH-treated or control cultures, These results suggest that PTH-induced bone resorption is mediated, at least in part, by the indu ction of collagenase and gelatinase B mRNA in bone cells.