Canonical Notch activation in osteocytes causes osteopetrosis

Area of Science:

• Bone Biology
• Cell Signaling
• Skeletal Physiology

Background:

• Notch1 signaling has opposing effects on osteoblast lineage cells and osteocytes.
• Canonical Notch signaling (Rbpjκ-dependent) role in osteocyte function remains unclear.

Purpose of the Study:

• To investigate the role of canonical Notch signaling in osteocyte function.
• To elucidate the mechanisms by which Notch activation influences bone metabolism in osteocytes.

Main Methods:

• Generated Dmp1-Cre;Rbpjκ(Δ/Δ) mice to assess Rbpjκ dispensability in osteocytes.
• Utilized Dmp1-Cre;Rosa(Notch) mice to activate Notch signaling in osteocytes, with and without Rbpjκ inactivation.
• Analyzed skeletal phenotypes, bone resorption markers, and gene expression (Sost, Dkk1, Axin2, Tnfrsf11b, Tnfsf11).

Main Results:

• Rbpjκ is dispensable for normal osteocyte function.
• Notch activation in osteocytes significantly increased femoral trabecular bone volume.
• This increase was associated with reduced osteoclast numbers and bone resorption, mediated by canonical Notch signaling.
• Notch activation downregulated Sost and Dkk1, and upregulated Axin2, Tnfrsf11b, and Tnfsf11 mRNA expression.

Conclusions:

• Canonical Notch signaling in osteocytes suppresses bone resorption and increases bone volume.
• Notch activation inhibits Sost and Dkk1, thereby promoting Wnt signaling.
• These findings highlight a novel mechanism for regulating bone mass via osteocyte Notch signaling.