Thursday, January 28, 2010


Conditional Inactivation of TNFα-Converting Enzyme in Chondrocytes Results in an Elongated Growth Plate and Shorter Long Bones.

" we generated a Tace[aka ADAM17, Membrane-bound proteolytic TNF-a converting enzyme] mutant mouse in which Tace is conditionally disrupted in chondrocytes under the control of the Col2a1 promoter. These mutant mice were fertile and viable but all exhibited long bones that were approximately 10% shorter compared to those of wild-type animals. Tace mutant mice exhibited a longer hypertrophic zone in the growth plate, and there were fewer osteoclasts at the chondro-osseous junction in the Tace mutant mice than in their wild-type littermates. we found an increase in osteoprotegerin transcripts and a reduction in Rankl and Mmp-13 transcripts in the TACE-deficient cartilage, indicating that dysregulation of these genes is causally related to the skeletal defects in the Tace mutant mice.  phosphorylation of EGFR was significantly reduced in the cartilage tissue lacking TACE, and that suppression of EGFR signaling increases osteoprotegerin transcripts and reduces Rankl and Mmp-13 transcripts in primary chondrocytes. In accordance, chondrocyte-specific abrogation of Egfr{up in LSJL} in vivo resulted in skeletal defects nearly identical to those observed in the Tace mutant mice. Taken together, these data suggest that TACE-EGFR signaling in chondrocytes is involved in the turnover of the growth plate during postnatal development via the transcriptional regulation of osteoprotegerin, Rankl, and Mmp-13."

So the upregulation of Egfr may play a role in the LSJL lengthening effects.

" the growth plate in adult[8 weeks of age] Tace/Col2 mice appeared normal"

129Sv and C57Bl/6 mice were used.

It's also possible that the reduction of the TNFa converting enzyme increased circulating levels of TNF-alpha.

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