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Development of a Human Preclinical Model of Osteoclastogenesis from Peripheral Blood Monocytes Co-cultured with Breast Cancer Cell Lines
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Cabozantinib targets bone microenvironment modulating human osteoclast and osteoblast functions

Marco Fioramonti1, Daniele Santini1, Michele Iuliani1

  • 1Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.

Oncotarget
|February 23, 2017
PubMed

Insights

Cabozantinib directly inhibits osteoclast function and bone resorption. It also indirectly reduces bone resorption by altering osteoblast signaling, offering potential benefits for bone health in cancer patients.

Area of Science:

  • Oncology
  • Bone Biology
  • Pharmacology

Background:

  • Cabozantinib is a dual inhibitor of c-MET and VEGFR2, showing efficacy in castration-resistant prostate cancer and metastatic renal carcinoma.
  • The drug's impact on the bone microenvironment, particularly osteoclast and osteoblast function, remains incompletely understood.

Purpose of the Study:

  • To investigate the direct effects of cabozantinib on primary human osteoclasts and osteoblasts.
  • To elucidate the mechanisms by which cabozantinib influences bone remodeling processes.

Main Methods:

  • Osteoclasts were differentiated from human monocytes, and osteoblasts from human mesenchymal stem cells.
  • Assays included tartrate-resistant acid phosphatase (TRAP) staining, bone resorption assays, alkaline phosphatase staining, and alizarin red staining.
  • Gene and protein expression of key markers (TRAP, Cathepsin K, RANK, OPG, RANKL) were analyzed.

Main Results:

  • Cabozantinib significantly inhibited osteoclast differentiation and bone resorption activity at non-cytotoxic doses.
  • The drug down-modulated key osteoclast marker genes: TRAP, Cathepsin K, and RANK.
  • Cabozantinib increased osteoprotegerin (OPG) and decreased Receptor Activator of Nuclear Factor k B Ligand (RANKL) in osteoblasts, reducing the RANKL/OPG ratio.

Conclusions:

  • Cabozantinib exerts direct inhibitory effects on osteoclast differentiation and function.
  • The drug also exhibits indirect anti-resorptive effects by modulating osteoblast OPG and RANKL expression.
  • These findings highlight cabozantinib's potential to favorably impact the bone microenvironment in cancer patients.
Keywords:
bone microenvironmentcabozantinibhuman primary cellsosteoprotegerin (OPG)receptor activator of nuclear factor-kb ligand (RANKL)

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