Conditional deletion of Tgfbr2 in hypertrophic chondrocytes delays terminal chondrocyte differentiation

• Published in: Matrix biology Vol. 31; no. 6; pp. 352 - 359
• Main Authors: Sueyoshi, Tatsuya, Yamamoto, Koji, Akiyama, Haruhiko
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2012
• Subjects: Animals; Bone and Bones - embryology; Bone and Bones - metabolism; Bone and Bones - pathology; Cell Differentiation; Cell Line; Chondrocytes - metabolism; Chondrocytes - pathology; Chondrocytes - physiology; Collagen Type II - genetics; Collagen Type II - metabolism; Collagen Type X - genetics; Collagen Type X - metabolism; Conditional knockout; Gene Deletion; Gene Expression; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hedgehog Proteins - physiology; Hypertrophic chondrocyte; Hypertrophy - metabolism; Indian hedgehog; Mice; Mice, Transgenic; Osteogenesis; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Tgfbr2; Tissue Culture Techniques; Transforming Growth Factor beta1 - physiology; Hypertrophic chondrocyte; Indian hedgehog; Conditional knockout; Tgfbr2
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2012.07.002

Transforming growth factor β (Tgfb) signaling plays an important role in endochondral ossification. Previous studies of mice in which the Tgfb type II receptor gene (Tgfbr2) was deleted in the limb bud mesenchymal cells or differentiated chondrocytes showed defects in the development of the long bones or the axial skeleton, respectively. Here, we generated mouse embryos in which the Tgfbr2 gene was ablated in hypertrophic chondrocytes. These mice exhibited delays in both the hypertrophic conversion of proliferating chondrocytes and the subsequent terminal chondrocyte differentiation. The expression domains of Col10a1, Matrix metalloproteinase 13, and Osteopontin were small, and the expression of Vascular endothelial growth factor and Platelet endothelial cell adhesion molecule was downregulated. The calcification of the bone collar in the mutant mice was markedly delayed and the periosteum was thin, possibly because of the downregulation of Indian hedgehog expression. We conclude that Tgfb signaling in hypertrophic chondrocytes positively regulates terminal chondrocyte differentiation, angiogenesis in calcified cartilage, and osteogenesis in the bone collar, at least partly through Indian hedgehog signaling in vivo.
► We generate mice in which the Tgfbr2 gene was ablated in hypertrophic chondrocytes. ► Hypertrophic conversion and terminal chondrocyte differentiation are delayed. ► Osteogenesis in the bone collar is markedly delayed. ► Tgfb signaling in hypertrophic chondrocytes regulates Indian hedgehog signaling.