Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
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.
Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
Kenta
K
Saito
Keisuke
K
Horiuchi
Tokuhiro
T
Kimura
Sakiko
S
Mizuno
Masaki
M
Yoda
Hideo
H
Morioka
Haruhiko
H
Akiyama
David
D
Threadgill
Yasunori
Y
Okada
Yoshiaki
Y
Toyama
Kazuki
K
Sato
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D001846:Bone Development / Q000235:genetics*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism / Q000502:physiology; D024043:Collagen Type II / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000254:growth & development / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D009154:Mutation; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D053244:Osteoprotegerin; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse