Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2

Héctor F. Araya, Hugo Sepulveda, Carlos O. Lizama, Oscar A. Vega, Sofia Jerez, Pedro F. Briceño, Roman Thaler, Scott M. Riester, Marcelo Antonelli, Flavio Salazar-Onfray, Juan Pablo Rodríguez, Ricardo D. Moreno, Martin Montecino, Martine Charbonneau, Claire M. Dubois, Gary S. Stein, Andre J van Wijnen, Mario A. Galindo

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8204-8219
Number of pages16
JournalJournal of Cellular Biochemistry
Volume119
Issue number10
DOIs
StatePublished - Nov 1 2018

Fingerprint

Osteoblasts
Osteosarcoma
Bone
Peptide Hydrolases
Transcription Factors
Bone and Bones
Paracrine Communication
Metalloproteases
Cell Communication
Tumor Necrosis Factor-alpha
Genes
RNA Sequence Analysis
Disintegrins
Extracellular Matrix Proteins
Bone Development
Cell membranes
Microarrays
ADAM17 Protein
Genetic Promoter Regions
Intercellular Signaling Peptides and Proteins

Keywords

  • ADAM genes
  • ADAM17
  • osteoblast differentiation
  • RUNX2
  • transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2. / Araya, Héctor F.; Sepulveda, Hugo; Lizama, Carlos O.; Vega, Oscar A.; Jerez, Sofia; Briceño, Pedro F.; Thaler, Roman; Riester, Scott M.; Antonelli, Marcelo; Salazar-Onfray, Flavio; Rodríguez, Juan Pablo; Moreno, Ricardo D.; Montecino, Martin; Charbonneau, Martine; Dubois, Claire M.; Stein, Gary S.; van Wijnen, Andre J; Galindo, Mario A.

In: Journal of Cellular Biochemistry, Vol. 119, No. 10, 01.11.2018, p. 8204-8219.

Research output: Contribution to journalArticle

Araya, HF, Sepulveda, H, Lizama, CO, Vega, OA, Jerez, S, Briceño, PF, Thaler, R, Riester, SM, Antonelli, M, Salazar-Onfray, F, Rodríguez, JP, Moreno, RD, Montecino, M, Charbonneau, M, Dubois, CM, Stein, GS, van Wijnen, AJ & Galindo, MA 2018, 'Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2', Journal of Cellular Biochemistry, vol. 119, no. 10, pp. 8204-8219. https://doi.org/10.1002/jcb.26832
Araya, Héctor F. ; Sepulveda, Hugo ; Lizama, Carlos O. ; Vega, Oscar A. ; Jerez, Sofia ; Briceño, Pedro F. ; Thaler, Roman ; Riester, Scott M. ; Antonelli, Marcelo ; Salazar-Onfray, Flavio ; Rodríguez, Juan Pablo ; Moreno, Ricardo D. ; Montecino, Martin ; Charbonneau, Martine ; Dubois, Claire M. ; Stein, Gary S. ; van Wijnen, Andre J ; Galindo, Mario A. / Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2. In: Journal of Cellular Biochemistry. 2018 ; Vol. 119, No. 10. pp. 8204-8219.
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AU - Araya, Héctor F.

AU - Sepulveda, Hugo

AU - Lizama, Carlos O.

AU - Vega, Oscar A.

AU - Jerez, Sofia

AU - Briceño, Pedro F.

AU - Thaler, Roman

AU - Riester, Scott M.

AU - Antonelli, Marcelo

AU - Salazar-Onfray, Flavio

AU - Rodríguez, Juan Pablo

AU - Moreno, Ricardo D.

AU - Montecino, Martin

AU - Charbonneau, Martine

AU - Dubois, Claire M.

AU - Stein, Gary S.

AU - van Wijnen, Andre J

AU - Galindo, Mario A.

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N2 - 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.

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