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TNFα-converting enzyme (TACE) is a membrane-bound proteolytic enzyme with essential roles in the functional regulation of TNFα and epidermal growth factor receptor (EGFR) ligands. Previous studies have demonstrated critical roles for TACE  in vivo , including epidermal development, immune response, and pathological neoangiogenesis, among others. However, the potential contribution of TACE to skeletal development is still unclear. In the present study, we generated a  Tace  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. Histological analyses revealed that  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. Of note, 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. Furthermore, we also found that 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 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 .

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