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J. Cell Biol.,
Volume 142, Number 4, August 24, 1998 1135-1144
* Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111; and We previously used subtractive hybridization
to isolate cDNAs for genes upregulated in chick hypertrophic chondrocytes (Nurminskaya, M., and T.F. Linsenmayer. 1996. Dev. Dyn. 206:260-271). Certain of
these showed homology with the "A" subunit of human
plasma transglutaminase (factor XIIIA), a member of a
family of enzymes that cross-link a variety of intracellular and matrix molecules. We now have isolated a full-length cDNA for this molecule, and confirmed that it is
avian factor XIIIA. Northern and enzymatic analyses
confirm that the molecule is upregulated in hypertrophic chondrocytes (as much as eightfold). The enzymatic analyses also show that appreciable transglutaminase activity in the hypertrophic zone becomes
externalized into the extracellular matrix. This externalization most likely is effected by cell death and subsequent lysis Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138
effected by the transglutaminase itself.
When hypertrophic chondrocytes are transfected with a
cDNA construct encoding the zymogen of factor
XIIIA, the cells convert the translated protein to a
lower molecular weight form, and they initiate cell
death, become permeable to macromolecules and eventually undergo lysis. Non-hypertrophic cells transfected
with the same construct do not show these degenerative
changes. These results suggest that hypertrophic chondrocytes have a novel, tissue-specific cascade of mechanisms that upregulate the synthesis of plasma transglutaminase and activate its zymogen. This produces
autocatalytic cell death, externalization of the enzyme,
and presumably cross-linking of components within the
hypertrophic matrix. These changes may in turn regulate the removal and/or calcification of this hypertrophic matrix, which are its ultimate fates.
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