NDR2 is critical for osteoclastogenesis by regulating ULK1-mediated mitophagy

Area of Science:

• Cell Biology
• Molecular Biology
• Bone Biology

Background:

• Bone homeostasis relies on osteoblast and osteoclast balance.
• Increased osteoclast activity is a key cause of bone loss.
• Nuclear Dbf2-related kinase (NDR2), a serine/threonine kinase, is part of the Hippo family.

Purpose of the Study:

• To investigate the role of NDR2 in osteoclast differentiation and bone homeostasis.
• To explore the therapeutic potential of the NDR2 pathway in bone loss conditions.

Main Methods:

• Assessed NDR2 expression during osteoclast differentiation.
• Utilized gene knockdown and overexpression to manipulate NDR2 levels.
• Generated and analyzed myeloid NDR2-deficient mice.
• Investigated the mechanism involving autophagy and mitophagy via ULK1.
• Examined the association between NDR2 expression and osteoporosis in patients.

Main Results:

• NDR2 expression increased during osteoclast differentiation.
• NDR2 negatively regulated osteoclastogenesis.
• NDR2 deficiency in myeloid cells led to reduced bone mass and exacerbated bone loss.
• NDR2 promoted autophagy and mitophagy by mediating ULK1 instability.
• ULK1 inhibition rescued bone loss in NDR2-deficient mice.
• Lower NDR2 expression correlated with increased osteoporosis incidence in patients.

Conclusions:

• NDR2 acts as a negative regulator of osteoclastogenesis.
• The NDR2/ULK1/mitophagy axis plays a critical role in maintaining bone mass.
• This pathway represents a potential therapeutic target for preventing and managing bone loss and osteoporosis.