期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 119, 期 10, 页码 8204-8219出版社
WILEY
DOI: 10.1002/jcb.26832
关键词
ADAM genes; ADAM17; osteoblast differentiation; RUNX2; transcriptional regulation
资金
- National Institutes of Health [R01 AR049069, P01 CA082834]
- Scientific and Technological Development Support Fund (FONDEF, Chile) [ID16110148]
- Millennium Science Initiative From Ministry for Economy, Development and Tourism, Chile [P09/016F]
- National Fund for Scientific and Technological Development (FONDECYT, Chile) [1095234, 1130931, 1130706, 1171213, 1160214, 1110778, 1150352]
- Fund for Research Centers in Priority Areas (FONDAP, Chile) [15090007]
- NATIONAL CANCER INSTITUTE [P01CA082834] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR049069] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U54GM115516] Funding Source: NIH RePORTER
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 (TNF alpha) converting enzyme also called (TACE), regulates TNF alpha-signaling pathway, which inhibits osteoblast differentiation. We demonstrate that Adam17 expression is suppressed by RUNX2 during osteoblast differentiation through the proximal Adam17 promoter region (-0.4kb) 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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