title: Parathyroid hormone inhibits the expression of membrane-type matrix metalloproteinase-1 (MT1-MMP) in osteoblast-like MG-63 cells.
abstract: 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.
authors.affiliation: Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, 86 Middle Renmin Road, Changsha, Hunan, PR China. xianghangluo@21cn.com
authors.forename: Xiang-hang
authors.initials: XH
authors.lastname: Luo
authors.forename: Er-yuan
authors.initials: EY
authors.lastname: Liao
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.forename: Xian-ping
authors.initials: XP
authors.lastname: Wu
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008562:Membrane Glycoproteins / Q000235:genetics; D008666:Metalloendopeptidases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides; D019379:Teriparatide / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013449:Sulfonamides; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D019379:Teriparatide; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D019311:Staurosporine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide