FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia.
FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12-ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12-ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12-ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12-ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia.
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Xiaofeng
X
Wang
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Huabing
H
Qi
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Quan
Q
Wang
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Ying
Y
Zhu
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Xianxing
X
Wang
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Min
M
Jin
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Qiaoyan
Q
Tan
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Qizhao
Q
Huang
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Wei
W
Xu
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Xiaogang
X
Li
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Liang
L
Kuang
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Yubing
Y
Tang
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Xiaolan
X
Du
d Department of Biochemistry ; Rush University Medical Center ; Chicago , IL USA.
Di
D
Chen
a Center of Bone Metabolism and Repair (CBMR); Trauma Center; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.|b State Key Laboratory of Trauma; Burns and Combined Injury; Third Military Medical University ; Chongqing , China.|c Department of Rehabilitation Medicine ; Institute of Surgery Research; Daping Hospital; Third Military Medical University ; Chongqing , China.
Lin
L
Chen
ATG12–ATG5 conjugate; FGFR3; achondroplasia; autophagy; chondrocytes