Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2

Area of Science:

• Bone Biology
• Cancer Biology
• Molecular Signaling

Background:

• Multiple myeloma (MM) is characterized by osteolytic bone lesions, impacting patient quality of life and survival.
• The osteoclast (OC)/osteoblast (OB) axis dysfunction is central to myeloma-associated bone disease (MBD).
• Key pathways like RANKL/OPG and NF-κB are implicated in MBD pathogenesis.

Purpose of the Study:

• To review the role of Nuclear factor erythroid 2-related factor 2 (NRF2) in regulating bone metabolism within the context of MBD.
• To elucidate NRF2's impact on osteoclasts (OCs) and osteoblasts (OBs) in myeloma bone disease.
• To understand how NRF2 influences cellular interactions and inflammatory signaling in MBD.

Main Methods:

• Literature review focusing on NRF2's function in bone cells and myeloma.
• Analysis of signaling pathways regulated by NRF2, including inflammatory and oxidative stress pathways.
• Examination of NRF2's effects on osteoclastogenesis and osteoblast function in MBD models.

Main Results:

• Loss of NRF2 in OCs reduces bone mass, affecting RANK/RANKL signaling and osteoclastogenesis.
• NRF2 levels in OBs can modulate interleukin-6 (IL-6) expression, influencing bone metabolism and myeloma cells.
• NRF2 activity in myeloma and stromal cells impacts inflammatory/ROS levels, affecting OCs, OBs, and osteocytes.

Conclusions:

• NRF2 plays a significant role in regulating bone metabolism and cellular crosstalk in MBD.
• NRF2's anti-inflammatory and antioxidant properties influence osteoclast and osteoblast function.
• Targeting NRF2 may offer therapeutic potential for managing myeloma-associated bone disease.