Parathyroid hormone inhibits the expression of membrane-type matrix metalloproteinase-1 (MT1-MMP) in osteoblast-like MG-63 cells.

Parathyroid hormone (PTH) can stimulate bone resorption by increasing the activity and the number of osteoclasts in bone tissue by several mechanisms. Recently, osteoblast-derived membrane-type matrix metalloproteinase-1 (MT1-MMP) has been implied to play an important role in the process of bone resorption by degrading bone matrix. In the present study, we observed the effects of PTH (1-34) on MT1-MMP production, and the role of the protein kinase A (PKA) and protein kinase C (PKC) pathways in the regulation of MT1-MMP in cultures of human osteoblast-like MG-63 cells. By Northern blot and Western immunoblot analysis, we found, unexpectedly, that PTH (1-34) inhibited MT1-MMP mRNA and protein expression in a dose- and time-dependent manner in MG-63 cells. The PKA antagonist H-89 blunted PTH (1-34)-mediated decreases in MT1-MMP protein synthesis. Forskolin, a PKA agonist, decreased MT1-MMP expression, which was similar to the action of PTH on MT1-MMP expression, in MG-63 cells. Staurosporine, a PKC inhibitor, also blocked the inhibition by PTH. We suggest that both the PKA and PKC pathways are involved in MT1-MMP downregulation by PTH. Furthermore, we found that PTH (1-34) induced the expression of receptor activator of nuclear factor (NF)-KappaB ligand (RANKL) mRNA in a dose- and time-dependent manner in MG-63 cells, and this effect of PTH on RANKL mRNA expression was nearly parallel to the effects of MT1-MMP downregulation, implying a correlation between MT1-MMP and RANKL expression. Our findings suggest that the decreased MT1-MMP expression induced by PTH may be involved in RANKL signaling in osteoblasts, and may play a role in the activation of bone resorption.