@article{6be2a3d716a543b58a5fd1c558789aa0,
title = "Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2",
abstract = "Osteoblast differentiation is controlled by transcription factor RUNX2 which temporally activates or represses several bone-related genes, including those encoding extracellular matrix proteins or factors that control cell-cell, and cell-matrix interactions. Cell-cell communication in the many skeletal pericellular micro-niches is critical for bone development and involves paracrine secretion of growth factors and morphogens. This paracrine signaling is in part regulated by “A Disintegrin And Metalloproteinase” (ADAM) proteins. These cell membrane-associated metalloproteinases support proteolytic release (“shedding”) of protein ectodomains residing at the cell surface. We analyzed microarray and RNA-sequencing data for Adam genes and show that Adam17, Adam10, and Adam9 are stimulated during BMP2 mediated induction of osteogenic differentiation and are robustly expressed in human osteoblastic cells. ADAM17, which was initially identified as a tumor necrosis factor alpha (TNFα) converting enzyme also called (TACE), regulates TNFα-signaling pathway, which inhibits osteoblast differentiation. We demonstrate that Adam17 expression is suppressed by RUNX2 during osteoblast differentiation through the proximal Adam17 promoter region (−0.4 kb) containing two functional RUNX2 binding motifs. Adam17 downregulation during osteoblast differentiation is paralleled by increased RUNX2 expression, cytoplasmic-nuclear translocation and enhanced binding to the Adam17 proximal promoter. Forced expression of Adam17 reduces Runx2 and Alpl expression, indicating that Adam17 may negatively modulate osteoblast differentiation. These findings suggest a novel regulatory mechanism involving a reciprocal Runx2-Adam17 negative feedback loop to regulate progression through osteoblast differentiation. Our results suggest that RUNX2 may control paracrine signaling through regulation of ectodomain shedding at the cell surface of osteoblasts by directly suppressing Adam17 expression.",
keywords = "ADAM genes, ADAM17, osteoblast differentiation, RUNX2, transcriptional regulation",
author = "Araya, {H{\'e}ctor F.} and Hugo Sepulveda and Lizama, {Carlos O.} and Vega, {Oscar A.} and Sofia Jerez and Brice{\~n}o, {Pedro F.} and Roman Thaler and Riester, {Scott M.} and Marcelo Antonelli and Flavio Salazar-Onfray and Rodr{\'i}guez, {Juan Pablo} and Moreno, {Ricardo D.} and Martin Montecino and Martine Charbonneau and Dubois, {Claire M.} and Stein, {Gary S.} and {van Wijnen}, {Andre J.} and Galindo, {Mario A.}",
note = "Funding Information: National Institutes of Health, Grant numbers: R01 AR049069, P01 CA082834; Scientific and Technological Development Support Fund (FONDEF, Chile), Grant number: ID16110148; Millennium Science Initiative From Ministry for Economy, Development and Tourism, Chile, Grant number: P09/016F; National Fund for Scientific and Funding Information: Technological Development (FONDECYT, Chile), Grant numbers: 1095234, 1130931, 1130706, 1171213, 1160214, 1110778, 1150352; Fund for Research Centers in Priority Areas (FONDAP, Chile), Grant number: 15090007 Funding Information: We thank the members of our research groups, including Mariana Osorio, Francisco Villanueva, Andres Stevenson, Nelson Varela (University of Chile) for stimulating discussions. This study was supported by National Fund for Scientific and Technological Development (FONDECYT Chile), grant numbers 1095234 and 1130931 (to MAG), 1130706 (to MM), 1171213 (to FS-O), 1160214 (to JPR), 1110778 and 1150352 (to RDM); Fund for Research Centers in Prioritary Areas (FONDAP Chile), grant number 15090007 (to MM); The Scientific and Technological Development Support Fund (FONDEF Chile), grant number ID16110148 (to FS-O); and Millennium Science Initiative from Ministry for the Economy, Development and Tourism, Chile, grant number P09/016-F (to MAG and FS-O). Additional support was provided by PhD fellowship of the National Commission for Scientific and Technological Research (CONICYT Chile) (to SJ and HFA). This work was also supported by National Institutes of Health Grants R01 AR049069 (to AJvW) and P01 CA082834 (to GSS). Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",
year = "2018",
month = nov,
day = "1",
doi = "10.1002/jcb.26832",
language = "English",
volume = "119",
pages = "8204--8219",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",
number = "10",
}