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NDR2 is critical for osteoclastogenesis by regulating ULK1-mediated mitophagy
Xiangxi Kong, … , Bao Huang, Jian Chen
Xiangxi Kong, … , Bao Huang, Jian Chen
Published November 19, 2024
Citation Information: JCI Insight. 2025;10(1):e180409. https://doi.org/10.1172/jci.insight.180409.
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Research Article Development Metabolism

NDR2 is critical for osteoclastogenesis by regulating ULK1-mediated mitophagy

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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 7

ULK1-IN2 rescued bone mass loss in both OVX model and Lysm+NDR2fl/fl mice.

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ULK1-IN2 rescued bone mass loss in both OVX model and Lysm+NDR2fl/fl mic...
(A) Schematic diagram of the model. Eight-week-old WT female mice underwent ovariectomy (OVX), followed by i.p. injection of ULK1-IN2 (0.5 mg/kg) on the second day after surgery, administered 3 times per week for a duration of 8 weeks. On day 56, the mice were euthanized to obtain tissue samples for subsequent experiments. (B) Representative 2D and 3D μCT images of the femur were obtained. (C) Statistical analysis was conducted on bone mass parameters of the femur (n = 6). (D) Histological staining using H&E and TRAP staining was performed on sections of the femur. (E) Histomorphological analysis of TRAP staining (n = 6). (F) Double-labeled calcein fluorescence image. Mice were i.p. injected with calcein staining solution on days 3 and 10 before sacrifice. (G) Statistical analysis of mineralization rate (n = 6). (H) Schematic diagram of the model. Six-week-old Lysm+NDR2fl/fl mice were i.p. administered ULK1-IN2 (0.5 mg/kg) 3 times per week for a duration of 4 weeks, following which the mice were euthanized to obtain tissue samples for subsequent experimental analysis. (I) Representative 2D and 3D images of femur. (J) Statistical analysis of femoral bone mass parameters (n = 6). (K) H&E staining and TRAP staining of femur sections. (L and M) Histomorphological analysis of TRAP staining (n = 6). (N) Double-labeled calcein fluorescence image. (O) Statistical analysis of mineralization rate (n = 6). Statistical analyses were determined by 2-tailed Student’s t test (J, L, and M), and 1-way ANOVA (C, E, and G). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Data were presented as mean ± SD.

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