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Mol. Cells 2011; 31(6): 573-578

Published online April 20, 2011

https://doi.org/10.1007/s10059-011-1055-x

© The Korean Society for Molecular and Cellular Biology

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

Hyun-Jung Park, Kyung Hwa Baek, Hye-Lim Lee, Arang Kwon, Hyo Rin Hwang, Abdul S. Qadir, Kyung Mi Woo, Hyun-Mo Ryoo, and Jeong-Hwa Baek*

Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Korea

Correspondence to : *Correspondence: baekjh@snu.ac.kr

Received: March 18, 2011; Revised: March 29, 2011; Accepted: March 29, 2011

Abstract

During orthodontic tooth movement, local hypoxia and enhanced osteoclastogenesis are observed in the com-pression side of periodontal tissues. The receptor activa-tor of nuclear factor-ĸB ligand (RANKL) is an osteoblast/ stromal cell-derived factor that is essential for osteoclas-togenesis. In this study, we examined the effect of hypoxia on RANKL expression in human periodontal ligament fibroblasts (PDLFs) to investigate the relationship between local hypoxia and enhanced osteoclastogenesis in the compression side of periodontal tissues. Hypoxia significantly enhanced the levels of RANKL mRNA and protein as well as hypoxia inducible factor-1α? (HIF-1α?) protein in PDLFs. Constitutively active HIF-1α? alone significantly increased the levels of RANKL expression in PDLFs under normoxic conditions, whereas dominant negative HIF-1α? blocked hypoxia-induced RANKL expression. To investi-gate further whether HIF-1α? directly regulates RANKL transcription, a luciferase reporter assay was performed using the reporter vector containing the RANKL promoter sequence. Exposure to hypoxia or overexpression of constitutively active HIF-1α? significantly increased RANKL promoter activity, whereas dominant negative HIF-1α? blocked hypoxia-induced RANKL promoter activity. Furthermore, mutations of putative HIF-1α? binding elements in RANKL promoter prevented hypoxia-induced RANKL promoter activity. The results of chromatin immunoprecipitation showed that hypoxia or constitutively active HIF-1α? increased the DNA binding of HIF-1α? to RANKL promoter. These results suggest that HIF-1α? mediates hypoxia-induced up-regulation of RANKL expression and that in compression side periodontal ligament, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in PDLFs.

Keywords hypoxia, hypoxia inducible factor-1α?, periodontal ligament fibroblasts, RANK Ligand

Article

Research Article

Mol. Cells 2011; 31(6): 573-578

Published online June 30, 2011 https://doi.org/10.1007/s10059-011-1055-x

Copyright © The Korean Society for Molecular and Cellular Biology.

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

Hyun-Jung Park, Kyung Hwa Baek, Hye-Lim Lee, Arang Kwon, Hyo Rin Hwang, Abdul S. Qadir, Kyung Mi Woo, Hyun-Mo Ryoo, and Jeong-Hwa Baek*

Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Korea

Correspondence to:*Correspondence: baekjh@snu.ac.kr

Received: March 18, 2011; Revised: March 29, 2011; Accepted: March 29, 2011

Abstract

During orthodontic tooth movement, local hypoxia and enhanced osteoclastogenesis are observed in the com-pression side of periodontal tissues. The receptor activa-tor of nuclear factor-ĸB ligand (RANKL) is an osteoblast/ stromal cell-derived factor that is essential for osteoclas-togenesis. In this study, we examined the effect of hypoxia on RANKL expression in human periodontal ligament fibroblasts (PDLFs) to investigate the relationship between local hypoxia and enhanced osteoclastogenesis in the compression side of periodontal tissues. Hypoxia significantly enhanced the levels of RANKL mRNA and protein as well as hypoxia inducible factor-1α? (HIF-1α?) protein in PDLFs. Constitutively active HIF-1α? alone significantly increased the levels of RANKL expression in PDLFs under normoxic conditions, whereas dominant negative HIF-1α? blocked hypoxia-induced RANKL expression. To investi-gate further whether HIF-1α? directly regulates RANKL transcription, a luciferase reporter assay was performed using the reporter vector containing the RANKL promoter sequence. Exposure to hypoxia or overexpression of constitutively active HIF-1α? significantly increased RANKL promoter activity, whereas dominant negative HIF-1α? blocked hypoxia-induced RANKL promoter activity. Furthermore, mutations of putative HIF-1α? binding elements in RANKL promoter prevented hypoxia-induced RANKL promoter activity. The results of chromatin immunoprecipitation showed that hypoxia or constitutively active HIF-1α? increased the DNA binding of HIF-1α? to RANKL promoter. These results suggest that HIF-1α? mediates hypoxia-induced up-regulation of RANKL expression and that in compression side periodontal ligament, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in PDLFs.

Keywords: hypoxia, hypoxia inducible factor-1α?, periodontal ligament fibroblasts, RANK Ligand

Mol. Cells
Sep 30, 2023 Vol.46 No.9, pp. 527~572
COVER PICTURE
Chronic obstructive pulmonary disease (COPD) is marked by airspace enlargement (emphysema) and small airway fibrosis, leading to airflow obstruction and eventual respiratory failure. Shown is a microphotograph of hematoxylin and eosin (H&E)-stained histological sections of the enlarged alveoli as an indicator of emphysema. Piao et al. (pp. 558-572) demonstrate that recombinant human hyaluronan and proteoglycan link protein 1 (rhHAPLN1) significantly reduces the extended airspaces of the emphysematous alveoli by increasing the levels of TGF-β receptor I and SIRT1/6, as a previously unrecognized mechanism in human alveolar epithelial cells, and consequently mitigates COPD.

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