Significance of NF-kappaB signaling and PARP1 activity in the TNF-induced inhibition of PHEX gene expression in human osteoblasts

Urszula Kędzierska; Łukasz Banasiak; Paweł Kiela; Paweł Marek Majewski

doi:10.18388/abp.2018_2633

Urszula Kędzierska Department of Animal Physiology, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland
Łukasz Banasiak Department of Molecular Phylogenetics and Evolution, Institute of Botany, Faculty of Biology and Biological and Chemical Research Centre, University of Warsaw, Zwirki i Wigury 101, 02-089 Warsaw, Poland
Paweł Kiela Departments of Pediatrics and Immunobiology, Steele Children’s Research Center, University of Arizona, Tucson AZ 85724, USA
Paweł Marek Majewski Department of Animal Physiology, Institute of Zoology, Faculty of Biology, University of Warsaw Miecznikowa 1, 02-096 Warsaw

DOI: https://doi.org/10.18388/abp.2018_2633

Abstract

Although loss of bone mineral density is a common symptom of chronic inflammatory diseases, its mechanisms are still poorly understood. The PHEX gene encodes a Zn-endopeptidase expressed in osteoblasts and contributes to bone mineralization. Data derived from rodents has indicated co-repression of the PHEX gene by the NF-κB pathway and poly(ADP-ribose) polymerase 1 (PARP1). The aim of this study was to determine the molecular mechanism involved in TNF-mediated downregulation of PHEX expression in human osteoblasts and human osteosarcoma cell line. We observed that activation of the NF-κB pathway by TNF was manifested as a nuclear increase in RELA and NFKB1 heterodimer. We found that TNF reduced PHEX expression and the proteasome inhibitor reversed this effect in osteosarcoma cell line. Contrary to the effects seen in rodents, inhibition of PARP1 enzymatic activity did not significantly reverse the effect of TNF on the human PHEX gene expression. EMSA studies showed that the number of adenines in the PHEX proximal promoter is crucial for the transcription factors’ interactions within that region. The obtained results support the hypothesis indicating the existence of a molecular mechanism of gene repression that involves a poly adenine-rich region of the proximal gene promoters and PARP1 transcriptional activity.

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