NDR2 is critical for the 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+NDR2f/f) 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 cKO-induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. In a word, NDR2-ULK1-mitophagy axis was a potential innovative therapeutic target for the prevention and management of bone loss.
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Research summary
The paper investigates the role of NDR2 in osteoclastogenesis and its implications for bone loss, which is a significant concern in aging populations. By elucidating the NDR2-ULK1-mitophagy axis and its potential as a therapeutic target for bone loss, the research contributes to understanding mechanisms that could mitigate age-related bone density decline. However, while the findings are solid and relevant to aging, they do not represent a major breakthrough or transformative impact on the field of longevity research.
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