RANKL is an essential cytokine mediator of polymethylmethacrylate particle-induced osteoclastogenesis

John C. Clohisy, Elfaridah Frazier, Teruhisa Hirayama, Yousef Abu-Amer

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


RANKL is a TNF superfamily member and an essential cytokine mediator of developmental osteoclastogenesis. We examined the role of RANKL in PMMA particle-induced osteoclastogenesis in vitro. In murine whole bone marrow cultures, PMMA particles stimulate a 2.5 fold increase in secreted RANKL, a 5-8 fold increase in osteoclast number and induce the formation of giant multinuclear osteoclasts. RANKL and TNF, potential cytokine mediators of PMMA, had similar osteoclastogenic effects. The RANKL inhibitor OPG was utilized to define the role of RANKL in mediating the PMMA response and was found to inhibit basal and PMMA particle-induced osteoclastogenesis. Additionally, particles stimulate osteoclast formation in RANKL-primed osteoclast precursor cells (devoid of supporting stromal cells) while RANKL untreated osteoclast precursors demonstrate no osteoclastogenic response to particles. Since TNF can potentiate RANKL action and is thought to mediate implant osteolysis we analyzed TNF-/- whole bone marrow cultures to elucidate the role of this cytokine. In TNF-/- cultures basal osteoclastogenesis remains intact, yet the PMMA effect is blunted. Finally, we show that PMMA, RANKL and TNF all activate the NF-kB and c-jun/AP-1 signaling pathways which are both fundamental to osteoclast formation and are potential sites of signal convergence in RANKL-mediated particle osteoclastogenesis.

Original languageEnglish
Pages (from-to)202-212
Number of pages11
JournalJournal of Orthopaedic Research
Issue number2
StatePublished - 2003


  • Implant particles
  • OPG
  • Osteoclast precursor cells
  • Osteoclastogenesis


Dive into the research topics of 'RANKL is an essential cytokine mediator of polymethylmethacrylate particle-induced osteoclastogenesis'. Together they form a unique fingerprint.

Cite this