Nmp4/CIZ contributes to fluid shear stress induced MMP-13 gene induction in osteoblasts

• Published in: Journal of cellular biochemistry Vol. 102; no. 5; pp. 1202 - 1213
• Main Authors: Charoonpatrapong-Panyayong, Kanokwan, Shah, Rita, Yang, Jieping, Alvarez, Marta, Pavalko, Fredrick M., Gerard-O'Riley, Rita, Robling, Alexander G., Templeton, Evan, Bidwell, Joseph P.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2007
• Subjects: 3T3 Cells; Animals; bone; Cell Culture Techniques; Cells, Cultured; Crk-Associated Substrate Protein - metabolism; Electrophoretic Mobility Shift Assay; Genes, Reporter; Luciferases - metabolism; Matrix Metalloproteinase 13 - biosynthesis; Matrix Metalloproteinase 13 - genetics; mechanical load; mechanosome; mechanotransduction; Mechanotransduction, Cellular; Mice; Nuclear Matrix-Associated Proteins - genetics; Nuclear Matrix-Associated Proteins - metabolism; Osteoblasts - cytology; Osteoblasts - metabolism; p130cas; Promoter Regions, Genetic; Protein Binding; RNA, Messenger - metabolism; Stress, Mechanical; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.21349

The expression of matrix metalloproteinase‐13 (MMP‐13), involved in bone turnover, is elevated in stretched MC3T3‐E1 osteoblast‐like cells. Strain‐mediated forces impact bone remodeling due in large part to the movement of fluid through the canalicular‐lacunar network. The resulting fluid shear stress (FSS) over the surface membranes of bone cells initiates bone remodeling. Although the nuclear events mediating putative FSS‐induced changes in osteoblast MMP‐13 transcription are unknown, previous studies with bone cells suggest an overlap between osteoblast FSS‐ and PTH‐induced signal response pathways. MMP‐13 PTH response is regulated by a 110 bp 5′ regulatory region, conserved across the mouse, rat, and human genes, that supports the binding of numerous transcription factors including Runx2, c‐fos/c‐jun, Ets‐1, and nuclear matrix protein 4/cas interacting zinc finger protein (Nmp4/CIZ) a nucleocytoplasmic shuttling trans‐acting protein that attenuates PTH‐driven transcription. Nmp4/CIZ also binds p130cas, an adaptor protein implicated in mechanotransduction. Here we sought to determine whether Nmp4/CIZ contributes to FSS‐induced changes in MMP‐13 transcription. FSS (12 dynes/cm2, 3–5 h) increased MMP‐13 promoter‐reporter activity approximately two‐fold in MC3T3‐E1 osteoblast‐like cells attended by a comparable increase in mRNA expression. This was accompanied by a decrease in Nmp4/CIZ binding to its cis‐element within the PTH response region, the mutation of which abrogated the MMP‐13 response to FSS. Interestingly, FSS enhanced Nmp4/CIZ promoter activity and induced p130cas nuclear translocation. We conclude that the PTH regulatory region of MMP‐13 also contributes to FSS response and that Nmp4/CIZ plays similar but distinct roles in mediating hormone‐ and FSS‐driven induction of MMP‐13 in bone cells. J. Cell. Biochem. 102: 1202–1213, 2007. © 2007 Wiley‐Liss, Inc.