Role of ANTXR1 in the regulation of RANKL-induced osteoclast differentiation and function.

Abstract

Anthrax toxin receptor 1 (ANTXR1) is a transmembrane protein with an extracellular domain which is deeply associated with the process of bone formation and plays an important role in angiogenesis. However, there have been no reports investigating the effects of ANTXR1 on bone metabolism mediated by the two types of bone cells, osteoclasts, and osteoblasts. The aim of this study is to reveal the role of ANTXR1 in the differentiation and function of osteoclasts and osteoblasts. We found that ANTXR1 positively regulated the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation and bone resorption with no effects on osteoblast differentiation by performing gain- and loss-of-function studies. During ANTXR1-mediated regulation of osteoclastogenesis, phosphorylation of early signal transducers such as c-Jun N-terminal kinase (JNK), Akt, inhibitor of kappa B (IκB), and phospholipase C gamma 2 (PLCγ2) was affected, which in turn altered the mRNA and protein levels of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). In addition, genetic manipulation of ANTXR1 in bone marrow macrophages (BMMs) modulated the capillary-like tube formation in HUVECs via secretion of two angiogenic factors, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor-A (VEGF-A). These results elucidated the importance of ANTXR1 in osteoclast differentiation and functional activity, as well as, osteoclast-mediated angiogenesis of endothelial cells. Taken together, we propose that ANTXR1 might be a promising candidate for gene therapy for bone metabolic diseases and further, might potentially serve as an important biomarker in the field of bone metastasis associated with vascularization.

• Authors: Jong Min Baek, Sung Chul Kwak, Kwon-Ha Yoon, Ju-Young Kim, Myeung Su Lee
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 510 Issue 2 Pg. 296-302 (03 05 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 30686531 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antxr1 protein, mouse
• Biomarkers, Tumor
• Fos protein, mouse
• Microfilament Proteins
• NFATC Transcription Factors
• Nfatc1 protein, mouse
• Proto-Oncogene Proteins c-fos
• RANK Ligand
• Receptors, Cell Surface
• Receptors, Peptide
• Tnfsf11 protein, mouse
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt
• I-kappa B Kinase
• MAP Kinase Kinase 4
• Phospholipase C gamma

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Bone Marrow Cells (cytology)
• Bone Resorption
• Cell Differentiation
• Cell Line
• Gene Silencing
• Genes, fos
• Human Umbilical Vein Endothelial Cells
• Humans
• I-kappa B Kinase (metabolism)
• MAP Kinase Kinase 4 (metabolism)
• Macrophages (cytology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Microfilament Proteins
• NFATC Transcription Factors (metabolism)
• Osteoblasts (cytology)
• Osteoclasts (cytology)
• Phospholipase C gamma (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• RANK Ligand (metabolism)
• Receptors, Cell Surface
• Receptors, Peptide (metabolism)