HIF alpha-1-mediated BMP6 down-regulation leads to hyperproliferation and abnormal differentiation of keratinocytes in vitro
EXPERIMENTAL DERMATOLOGY
Authors: Kim, Jin Hee; Bae, Hyun Cheol; Kim, Jaehyung; Lee, Hana; Ryu, Woo-In; Son, Eui Dong; Lee, Tae Ryong; Jeong, Sang Hoon; Son, Sang Wook
Abstract
Hypoxia-inducible factor-1 (HIF-1) has been reported to be up-regulated in psoriatic epidermis, resulting in increased proliferation and abnormal differentiation of human keratinocytes (KCs). However, the role of HIF-1 in psoriatic epidermis, which is mainly composed of KCs, is poorly understood. Here, we show that morphogenic protein 6 (BMP6) is down-regulated when HIF-1 is upregulated in patients with psoriasis skin lesions. HIF-1 overexpression in primary human KCs promoted proliferation and inhibited terminal differentiation. Furthermore, HIF1- repressed the expression of BMP6 by binding directly to the hypoxia-response element (HRE) in the BMP6 promotor region, which shows that BMP6 is a novel target gene of HIF-1. We also found that HIF-1-mediated BMP6 suppression could alter the proliferation status by modulating the expression levels of cell cycle regulatory proteins and also affect the early differentiation of KCs. Therefore, we suggest that HIF-1-dependent BMP6 suppression has a critical role in the induction of hyper-proliferation and abnormal differentiation in psoriatic KCs.
Bone morphogenetic protein 6 stimulates mineralization in human dental follicle cells without dexamethasone
ARCHIVES OF ORAL BIOLOGY
Authors: Takahashi, Kosuke; Ogura, Naomi; Aonuma, Haruna; Ito, Ko; Ishigami, Daisuke; Kamino, Yoshikazu; Kondoh, Toshirou
Abstract
Objective: The aim of this study is to investigate the osteogenic differentiation human dental follicle cells (hDFCs) cultured with in osteogenic induction medium (OIM) without dexamethasone (DEX), and to analyze the gene expression profile during osteogenic differentiation. Methods: hDFCs, which isolated from dental follicle tissue from impacted third molar teeth, were cultured with OIM with or without DEX. Osteogenic differentiation of hDFCs was examined using Alkaline phosphatase activity and Arizarin red staining. Gene expression analysis was performed by Microarray and real time-PCR. Results: We showed that hDFCs have the capacity to differentiate into osteogenic lineages in osteogenic induction medium lacking DEX. We also analyzed gene expression profiling of hDFCs during osteogenic differentiation. BMP6 is up-regulated in both the presence and absence of DEX. In addition, BMP6 enhances gene expression levels of DLX-5, Runx2, and Osterix, which are transcription factors associated with osteogenic differentiation. BMP6 also stimulates phosphorylation of Smad1/5/8 which are transcription factors associated with BMP signalling at protein levels. Additionally BMP6 stimulates mineralization of hDFCs monolayers examined by Arizarin red S staining. Conclusion: These findings suggest that hDFCs can differentiate to osteogenic lineage cells osteogenic induction medium without DEX, and BMP6 is a key gene in the osteogenic differentiation of hDFCs, and has therapeutic utility for bone regeneration and bone research. (C) 2012 Elsevier Ltd. All rights reserved.