Discoidin domain receptor 1 regulates endochondral ossification through terminal differentiation of chondrocytes

• Published in: The FASEB journal Vol. 34; no. 4; p. 5767
• Main Authors: Chou, Liang-Yin, Chen, Chung-Hwan, Lin, Yi-Hsiung, Chuang, Shu-Chun, Chou, Hsin-Chiao, Lin, Sung-Yen, Fu, Yin-Chi, Chang, Je-Ken, Ho, Mei-Ling, Wang, Chau-Zen
• Format: Journal Article
• Language: English
• Published: United States 01.04.2020
• Subjects: Animals; Bone and Bones - cytology; Cell Differentiation; Chondrocytes - cytology; Chondrocytes - metabolism; Chondrogenesis; Discoidin Domain Receptor 1 - physiology; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteogenesis; DDR1; chondrocytes; endochondral ossification; skeletal development; discoidin domain receptor 1
• ISSN: 1530-6860
• DOI: 10.1096/fj.201901852RR

Chondrocytes in growth plates are responsible for longitudinal growth in long bones during endochondral ossification. Discoidin domain receptor 1 (Ddr1) is expressed in chondrocytes, but the molecular mechanisms by which DDR1 regulates chondrocyte behaviors during the endochondral ossification process remain undefined. To elucidate Ddr1-mediate chondrocyte functions, we generated chondrocyte-specific Ddr1 knockout (CKOΔDdr1) mice in this study. The CKOΔDdr1 mice showed delayed development of the secondary ossification center and increased growth plate length in the hind limbs. In the tibial growth plate in CKOΔDdr1 mice, chondrocyte proliferation was reduced in the proliferation zone, and remarkable downregulation of Ihh, MMP13, and Col-X expression in chondrocytes resulted in decreased terminal differentiation in the hypertrophic zone. Furthermore, apoptotic chondrocytes were reduced in the growth plates of CKOΔDdr1 mice. We concluded that chondrocytes with Ddr1 knockout exhibit decreased proliferation, terminal differentiation, and apoptosis in growth plates, which delays endochondral ossification and results in short stature. We also demonstrated that Ddr1 regulates the Ihh/Gli1/Gli2/Col-X pathway to regulate chondrocyte terminal differentiation. These results indicate that Ddr1 is required for chondrocytes to regulate endochondral ossification in skeletal development.