title: Sirtuin 1 is a negative regulator of parathyroid hormone stimulation of matrix metalloproteinase 13 expression in osteoblastic cells: role of sirtuin 1 in the action of PTH on osteoblasts.
abstract: Parathyroid hormone (PTH) is the only current anabolic treatment for osteoporosis in the United States. PTH stimulates expression of matrix metalloproteinase 13 (MMP13) in bone. Sirtuin 1 (SIRT1), an NAD-dependent deacetylase, participates in a variety of human diseases. Here we identify a role for SIRT1 in the action of PTH in osteoblasts. We observed increased Mmp13 mRNA expression and protein levels in bone from Sirt1 knock-out mice compared with wild type mice. PTH-induced Mmp13 expression was significantly blocked by the SIRT1 activator, resveratrol, in osteoblastic UMR 106-01 cells. In contrast, the SIRT1 inhibitor, EX527, significantly enhanced PTH-induced Mmp13 expression. Two h of PTH treatment augmented SIRT1 association with c-Jun, a component of the transcription factor complex, activator protein 1 (AP-1), and promoted SIRT1 association with the AP-1 site of the Mmp13 promoter. This binding was further increased by resveratrol, implicating SIRT1 as a feedback inhibitor regulating Mmp13 transcription. The AP-1 site of the Mmp13 promoter is required for PTH stimulation of Mmp13 transcriptional activity. When the AP-1 site was mutated, EX527 was unable to increase PTH-stimulated Mmp13 promoter activity, indicating a role for the AP-1 site in SIRT1 inhibition. We further showed that SIRT1 deacetylates c-Jun and that the cAMP pathway participates in this deacetylation process. These data indicate that SIRT1 is a negative regulator of MMP13 expression, SIRT1 activation inhibits PTH stimulation of Mmp13 expression, and this regulation is mediated by SIRT1 association with c-Jun at the AP-1 site of the Mmp13 promoter.
authors: From the Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 and.
authors: Yurong
authors: Y
authors: Fei
authors: From the Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 and.
authors: Emi
authors: E
authors: Shimizu
authors: the Ottawa Health Research Center Institute, Ottawa, Ontario K1H 8L6, Canada.
authors: Michael W
authors: MW
authors: McBurney
authors: From the Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 and ncp234@nyu.edu.
authors: Nicola C
authors: NC
authors: Partridge
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D004790:Enzyme Induction; D005260:Female; D005269:Femur / Q000166:cytology / Q000201:enzymology; D015870:Gene Expression; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000201:enzymology*; D010281:Parathyroid Hormone / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D056564:Sirtuin 1 / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: AP1 Transcription Factor (AP-1); Matrix Metalloproteinase (MMP); Osteoblast; PTH; Parathyroid Hormone; Sirtuin 1 (SIRT1)
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