NDR2 is critical for osteoclastogenesis by regulating ULK1-mediated mitophagy
Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiao-jian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen
Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiao-jian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen
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Research Article Development Metabolism

NDR2 is critical for osteoclastogenesis by regulating ULK1-mediated mitophagy

Abstract

Bone homeostasis primarily stems from the balance between osteoblasts and osteoclasts, wherein an augmented number or heightened activity of osteoclasts is a prevalent etiological factor in the development of bone loss. Nuclear Dbf2-related kinase (NDR2), also known as STK38L, is a member of the Hippo family with serine/threonine kinase activity. We unveiled an upregulation of NDR2 expression during osteoclast differentiation. Manipulation of NDR2 levels through knockdown or overexpression facilitated or hindered osteoclast differentiation, respectively, indicating a negative feedback role for NDR2 in the osteoclastogenesis. Myeloid NDR2-dificient mice (Lysm+NDR2fl/fl) showed lower bone mass and further exacerbated ovariectomy-induced or aging-related bone loss. Mechanically, NDR2 enhanced autophagy and mitophagy through mediating ULK1 instability. In addition, ULK1 inhibitor (ULK1-IN2) ameliorated NDR2 conditional KO–induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. The NDR2/ULK1/mitophagy axis is a potential innovative therapeutic target for the prevention and management of bone loss.

Authors

Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiao-jian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen

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Figure 3

Lysm+NDR2fl/fl mice aggravated OVX-induced and aging-related bone loss.

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Lysm+NDR2fl/fl mice aggravated OVX-induced and aging-related bone loss....
(A) OVX was performed on 2-month-old Lysm–NDR2fl/fl and Lysm+NDR2fl/fl mice, and the mice were sacrificed after 8 weeks for femur sample collection. μCT was utilized to illustrate the alterations in femoral trabeculae. (B) Analysis of parameters associated with trabecular bone in the proximal femur was conducted (n = 6). (C) H&E staining and TRAP staining were performed on sections of the femur. (D and E) Histomorphological analysis of TRAP staining was carried out (n = 6). (F) Representative μCT images of 18-month-old Lysm–NDR2fl/fl and Lysm+NDR2fl/fl mouse femurs. (G) Analysis of parameters related to trabecular bone in the proximal femur (n = 6). (H) H&E staining and TRAP staining were conducted on sections of the femur. (I) Histomorphological analysis of TRAP staining (n = 6). Statistical analyses were determined by 2-tailed Student’s t test (G and I), and 2-way ANOVA (B, D, and E). ns indicated no statistical difference, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Data were presented as mean ± SD.