A novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma

Area of Science:

• Bone Oncology
• Hematologic Malignancies
• Cell Signaling

Background:

• Multiple myeloma (MM) causes significant bone disease, characterized by osteolytic destruction.
• Osteolytic lesions in MM are driven by increased osteoclast activity and bone resorption.
• Osteocytes contribute to MM bone disease by overproducing RANKL, a key regulator of osteoclastogenesis.

Purpose of the Study:

• To elucidate the molecular mechanisms by which osteocytes dysregulate RANKL expression in the MM bone microenvironment.
• To investigate the role of MM-derived factors in promoting osteocytic RANKL upregulation and subsequent bone loss.

Main Methods:

• Utilized in vitro, ex vivo, and in vivo models, including human and murine osteocytes and MM cells.
• Employed genetic and pharmacologic inhibition strategies targeting CCL3.
• Analyzed clinical data and performed mechanistic studies to identify signaling pathways involved.

Main Results:

• MM-derived CCL3 was identified as a direct inducer of RANKL upregulation in osteocytes.
• Inhibition of CCL3 prevented RANKL upregulation and attenuated MM-induced bone loss.
• MM-derived CCL3 triggers osteocytic HMGB1 secretion, which is essential for RANKL upregulation.

Conclusions:

• A novel CCL3-HMGB1 signaling axis in the MM tumor niche promotes osteocytic RANKL overproduction.
• This pathway drives bone resorption and exacerbates bone disease in multiple myeloma.
• Targeting the CCL3-HMGB1 axis represents a potential therapeutic strategy for MM bone disease.