title: Angiotensin II induces the production of MMP-3 and MMP-13 through the MAPK signaling pathways via the AT(1) receptor in osteoblasts.
abstract: Angiotensin II (Ang II) plays an important role in the maintenance of bone mass and integrity by activation of the mitogen-activated protein kinases (MAPKs) and by modulation of balance between resorption by osteoclasts and formation by osteoblasts. However, the role of Ang II in the turnover of extracellular matrix (ECM) in osteoid by osteoblasts remains unclear. Therefore, we examined the effect of Ang II on the expression of matrix metalloproteinases (MMPs), plasminogen activators (PAs), and their inhibitors [i.e., tissue inhibitors of metalloproteinases (TIMPs) and PA inhibitor-1 (PAI-1)] using osteoblastic ROS17/2.8 cells. Treatment with Ang II strikingly increased the expressions of MMP-3 and -13 and promoted cell proliferation associated with reduced alkaline phosphatase activity as well as enhanced phosphorylated expression of extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) in ROS17/2.8 cells. However, Ang II had no effect on the expression of MMP-2, -9, -14, urokinase-type PA, tissue-type PA, TIMP-1, -2, -3, and PAI-1 in cells. Losartan (AT1 receptor blocker) blocked Ang II-induced expression of MMP-3 and -13, whereas PD123319 (AT2 receptor blocker) did not completely block these responses. Losartan also blocked the Ang II-induced phosphorylation of ERK1/2, p38 MAPK, and SAPK/JNK. MAPK kinase 1/2 inhibitor PD98059 and JNK inhibitor SP600125 suppressed Ang II-induced expression of MMP-3 and -13. These results suggested that Ang II stimulated the degradation process that occurs during ECM turnover in osteoid by increasing the production of MMP-3 and -13 through MAPK signaling pathways via the AT1 receptor in osteoblasts. Furthermore, our findings suggest that Ang II does not influence the plasminogen/plasmin pathway in osteoblasts.
authors.affiliation: Division of Oral Health Sciences, Nihon University Graduate School of Dentistry, 1-8-13, Kanda Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nakai
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawato
authors.forename: Toyoko
authors.initials: T
authors.lastname: Morita
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Iinuma
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kamio
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Masao
authors.initials: M
authors.lastname: Maeno
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005780:Gelatin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D010960:Plasminogen Activators / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics
chemical_list: D007093:Imidazoles; D017395:Plasminogen Activator Inhibitor 1; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D019714:Tissue Inhibitor of Metalloproteinases; D000804:Angiotensin II; C073402:PD 123319; D005780:Gelatin; D000469:Alkaline Phosphatase; D010960:Plasminogen Activators; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D019808:Losartan