Roxadustat Inhibits Osteoclast Differentiation and Function by Disrupting Cell Cycle Exit

Area of Science:

• Bone Biology
• Pharmacology
• Cellular Differentiation

Background:

• Bone remodeling requires a balance between osteoclast resorption and osteoblast formation.
• Roxadustat is known to promote osteoblast differentiation, but its effects on osteoclasts are not well understood.

Purpose of the Study:

• To investigate the impact of roxadustat on osteoclast differentiation and function in vitro.
• To elucidate the mechanisms underlying roxadustat's effects on osteoclasts.

Main Methods:

• Primary murine bone marrow-derived mononuclear cells were used.
• Osteoclast differentiation was induced with M-CSF and RANKL.
• Assays included cell viability, TRAP staining, bone resorption, RNA-seq, flow cytometry, immunofluorescence, Western blot, and rescue experiments with abemaciclib (a CDK4/6 inhibitor).

Main Results:

• Roxadustat suppressed osteoclast differentiation and resorption in a concentration-dependent manner without cytotoxicity.
• RNA-seq indicated enrichment of cell cycle pathways.
• Roxadustat paradoxically promoted osteoclast precursor proliferation, evidenced by increased Ki67 and decreased p27 expression.
• Abemaciclib partially reversed the inhibitory effects of roxadustat on osteoclastogenesis and resorption.

Conclusions:

• Roxadustat inhibits osteoclast differentiation, potentially by disrupting cell cycle exit and promoting precursor proliferation via p27 downregulation.
• Roxadustat's dual effects on osteoblasts and osteoclasts suggest therapeutic potential for bone disorders, especially in patients with renal anemia and osteoporosis.
• Further research is warranted to explore roxadustat's clinical application in bone diseases.