Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4

Eun Ju Chang, Hyon Jong Kim, Jeongim Ha, Hyung Joon Kim, Jiyoon Ryu, Kwang Hyun Park, Uh Hyun Kim, Zang Hee Lee, Hyun Man Kim, David E. Fisher, Hong Hee Kim

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


The differentiation of osteoclasts, cells specialized for bone resorption, is governed by two key factors, macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). The extracellular matrix (ECM) is an important factor influencing cell fate. To date, little investigation on the relationship between ECM components and osteoclast differentiation has been documented. In this study, we uncovered a potent anti-osteoclastogenic effect of hyaluronan (HA), an ECM component present in bone marrow and soft connective tissues, in primary mouse and human osteoclast precursor cell cultures. The anti-osteoclastogenic function of HA was dependent on Toll-like receptor 4 (TLR4) but not on CD44. HA inhibited M-CSF-dependent signaling pathways involving Rac, reactive oxygen species and mitogen-activated protein kinases, resulting in suppression of transcription factors AP-1 and MITF that control RANK expression. Furthermore, in an in vivo mouse model of calvarial bone resorption assays HA reduced RANKL-induced bone erosion and osteoclastogenesis. Our results clearly show that HA inhibits osteoclast differentiation through TLR4 by interfering with M-CSF signaling, and point that the interaction between ECM components and innate immune receptors can play an important role in the regulation of bone metabolism.

Original languageEnglish (US)
Pages (from-to)166-176
Number of pages11
JournalJournal of cell science
Issue number1
StatePublished - Jan 1 2007
Externally publishedYes


  • Hyaluronan
  • Macrophage colony stimulating factor
  • Osteoclast
  • Receptor activator of nuclear factor kappaB
  • Toll-like receptor

ASJC Scopus subject areas

  • Cell Biology


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