Research article summary (published 30 Dec 2001):

Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells.

Full Abstract

Osteoblasts secrete a complex extracellular matrix (ECM) containing collagenous and noncollagenous proteins, bone morphogenetic proteins (BMPs), and growth factors. Osteoblast-specific gene expression requires ascorbic acid (AA)-dependent assembly of a collagenous ECM. Matrix responsiveness requires an alpha2beta1 integrin-collagen interaction and mitogen-activated protein kinase (MAPK) activity, which phosphorylates and activates the osteoblast-specific transcription factor Cbfa1. This study examines interactions between this integrin/MAPK-mediated pathway and signals initiated by BMPs contained in the osteoblast matrix. MC3T3-E1 cells were shown to constitutively express BMP-2, BMP-4, and BMP-7. Noggin, a specific BMP inhibitor, reversibly blocked AA-induced gene expression, indicating that BMP production by MC3T3-E1 cells was necessary for differentiation. The ability of exogenously added BMP-2, BMP-4, or BMP-7 to stimulate osteocalcin (OCN) and bone sialoprotein (BSP) mRNAs or OCN promoter activity was synergistically increased in cells that were actively synthesizing an ECM (i.e., were grown in the presence of AA). A minimum of 4 days of ECM accumulation was required for this synergistic response to be observed. Neither BMP-7, AA, nor a combination of these two treatments had major effects on Cbfa1 messenger RNA (mRNA) or protein levels, as would be expected if regulation was mainly at the posttranscriptional level. U0126, a specific inhibitor of MAPK/extracellular signal-regulated kinase (MEK), blocked AA- or BMP-7/AA-dependent gene expression in a time- and dose-dependent manner that was closely correlated with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation. This work establishes that autocrine BMP production as well as integrin-mediated cell-collagen interactions are both required for osteoblast differentiation, and both these pathways require MAP kinase activity.

Author information

Author/s: Xiao, Guozhi (G); Gopalakrishnan, Rajaram (R); Jiang, Di (D); Reith, Elizabeth (E); Benson, M Douglas (MD); Franceschi, Renny T (RT);

Affiliation: Department of Periodontics, Prevention, and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor 48109-1078, USA.

Grants: DE 11723 (Agency:NIDCR NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, U.S. Gov't, P.H.S.

Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res), published in United States. (Language: eng)

Reference: 2002-Jan; vol 17 (issue 1) : pp 101-10

Dates: Created 2001/12/28; Completed 2002/06/17; Revised 2008/11/21;

PMID: 11771655, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

3T3 Cells Animals Ascorbic Acid - pharmacology Base Sequence Bone Morphogenetic Protein 2 Bone Morphogenetic Protein 4 Bone Morphogenetic Protein 7 Bone Morphogenetic Proteins - genetics; pharmacology Cell Differentiation Extracellular Matrix - metabolism

Extracellular Matrix - metabolism Gene Expression - drug effects Mice Mitogen-Activated Protein Kinases - metabolism Osteoblasts - cytology; drug effects; metabolism Osteocalcin - genetics RNA, Messenger - genetics; metabolism Sialoglycoproteins - genetics Signal Transduction Transforming Growth Factor beta

Associated Chemicals: Bmp2 protein, mouse (0) ; Bmp4 protein, mouse (0) ; Bone Morphogenetic Protein 2 (0) ; Bone Morphogenetic Protein 4 (0) ; Bone Morphogenetic Protein 7 (0) ; Bone Morphogenetic Proteins (0) ; RNA, Messenger (0) ; Sialoglycoproteins (0) ; Transforming Growth Factor beta (0) ; bone sialoprotein (0) ; Osteocalcin (104982-03-8) ; Ascorbic Acid (50-81-7) ; Mitogen-Activated Protein Kinases (EC 2.7.1.37)

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