Bone Biology Inhibiting Osteoclast Formation

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

Hyaluronic acid (hyaluronan, HA) is a component of the extracellular matrix and is also used clinically to treat joint and cartilage diseases such as osteoarthritis. Chang et al. show that high molecular mass HA (HMM-HA), but not low molecular mass HA, inhibited osteoclast differentiation of bone marrow-derived macrophages in response to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor B ligand (RANKL). HMM-HA did not block RANKL-stimulated osteoclastogenesis of RAW264.7 cells, which is independent of M-CSF. Although CD44 is one known receptor for HA, antibodies that block CD44 had no effect on the inhibition of osteoclast formation by HA. However, function-blocking antibodies against Toll-like receptor 4 (TLR4) blocked the inhibitory effect of HA, suggesting that HA was acting through the TLR4. TLR4-transfected cells bound labeled HA based on fluorescence-activated cell sorting analysis, and osteoclastogenesis of cells from mice with a nonfunctional TLR4 were not inhibited by HA. HA decreased signaling pathways activated by M-CSF but did not inhibit those activated by RANKL unless the cells were pretreated with HA for 2 days before RANKL exposure. HA decreased the production of reactive oxygen species stimulated by the receptor tyrosine kinase activated by M-CSF and also inhibited activation of Rac and downstream kinases of the mitogen-activated protein kinase family (p38, ERK, and JNK). HA reduced the abundance of RANK and appeared to mediate this effect by its inhibition of M-CSF signaling, because M-CSF leads to the phosphorylation and activation of two transcription factors for which binding sites exist in the RANK promoter. Thus, M-CSF may stimulate osteoclastogenesis by increasing the responsiveness to RANKL through increased abundance of the receptor RANK, and HA blocks this pathway. In a mouse model for bone erosion, implantation of collagen films containing RANKL in the presence or absence of HA onto mouse skulls showed that HA decreased the RANKL-induced bone loss. These results show a possible mechanism by which HA is clinically useful, expand the role of innate immune receptors to regulation of bone metabolism, and provide a potential connection between bone metabolism and the innate immune system.

E.-J. Chang, H. J. Kim. J. Ha, H. J. Kim, J. Ryu, K.-H. Park, U.-H. Kim, Z. H. Lee, H.-M. Kim, D. E. Fisher, H.-H. Kim, Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4. J. Cell Sci. 120, 166-176 (2007). [Abstract] [Full Text]

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