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Molecular and Cellular Biology, January 1999, p. 788-795, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Human Osteogenesis Involves Differentiation-Dependent Increases in the Morphogenically Active 3' Alternative Splicing Variant of Acetylcholinesterase

Dan Grisaru,1,2,3 Efrat Lev-Lehman,1,dagger Michael Shapira,1 Ellen Chaikin,1 Joseph B. Lessing,2 Amiram Eldor,3 Fritz Eckstein,4 and Hermona Soreq1,*

Department of Biological Chemistry, Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem 91904,1 and Departments of Obstetrics and Gynecology2 and Hematology,3 Tel-Aviv Sourasky Medical Center, The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel, and Max-Planck-Institut für Experimentelle Medizin, D-37075 Göttingen, Germany4

Received 15 May 1998/Returned for modification 14 July 1998/Accepted 21 September 1998

The extended human acetylcholinesterase (AChE) promoter contains many binding sites for osteogenic factors, including 1,25-(OH)2 vitamin D3 and 17beta -estradiol. In differentiating osteosarcoma Saos-2 cells, both of these factors enhanced transcription of the AChE mRNA variant 3' terminated with exon 6 (E6-AChE mRNA), which encodes the catalytically and morphogenically active E6-AChE isoform. In contrast, antisense oligodeoxynucleotide suppression of E6-AChE mRNA expression increased Saos-2 proliferation in a dose- and sequence-dependent manner. The antisense mechanism of action was most likely mediated by mRNA destruction or translational arrest, as cytochemical staining revealed reduction in AChE gene expression. In vivo, we found that E6-AChE mRNA levels rose following midgestation in normally differentiating, postproliferative fetal chondrocytes but not in the osteogenically impaired chondrocytes of dwarf fetuses with thanatophoric dysplasia. Taken together, these findings suggest morphogenic involvement of E6-AChE in the proliferation-differentiation balance characteristic of human osteogenesis.

* Corresponding author. Mailing address: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Phone: 972-2-6585109. Fax: 972-2-6520258. E-mail: Soreq{at}shum.huji.ac.il.

dagger Present address: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.

Molecular and Cellular Biology, January 1999, p. 788-795, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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