Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Cell Sci. 120 (1): 166-176

Research Article

Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4

Eun-Ju Chang1,*, Hyon Jong Kim1,*, Jeongim Ha1, Hyung Joon Kim1, Jiyoon Ryu1, Kwang-Hyun Park2, Uh-Hyun Kim2, Zang Hee Lee1, Hyun-Man Kim1, David E. Fisher3, and Hong-Hee Kim1,{ddagger}

1 Department of Cell and Developmental Biology and Brain Korea 21 Program, DRI, Seoul National University, Seoul 110-749, Korea
2 Department of Biochemistry and Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju 561-182, Korea
3 Division of Pediatric Hematology/Oncology and Melanoma Program in Medical Oncology, Dana-Farber Cancer Institute and Children's Hospital, Harvard Medical School, Boston, MA 02115, USA

{ddagger} Author for correspondence (e-mail: hhbkim{at}

Accepted for publication 20 October 2006.

Abstract: 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 {kappa}B 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.

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

Hyaluronan as an Immune Regulator in Human Diseases.
D. Jiang, J. Liang, and P. W. Noble (2011)
Physiol Rev 91, 221-264
   Abstract »    Full Text »    PDF »
Impaired osteoclastogenesis by staphylococcal lipoteichoic acid through Toll-like receptor 2 with partial involvement of MyD88.
J. Yang, Y. H. Ryu, C.-H. Yun, and S. H. Han (2009)
J. Leukoc. Biol. 86, 823-831
   Abstract »    Full Text »    PDF »
CD44-Epidermal Growth Factor Receptor Interaction Mediates Hyaluronic Acid-promoted Cell Motility by Activating Protein Kinase C Signaling Involving Akt, Rac1, Phox, Reactive Oxygen Species, Focal Adhesion Kinase, and MMP-2.
Y. Kim, Y.-S. Lee, J. Choe, H. Lee, Y.-M. Kim, and D. Jeoung (2008)
J. Biol. Chem. 283, 22513-22528
   Abstract »    Full Text »    PDF »
The JNK-dependent CaMK pathway restrains the reversion of committed cells during osteoclast differentiation.
E.-J. Chang, J. Ha, H. Huang, H. J. Kim, J. H. Woo, Y. Lee, Z. H. Lee, J. H. Kim, and H.-H. Kim (2008)
J. Cell Sci. 121, 2555-2564
   Abstract »    Full Text »    PDF »
Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization.
M. Shimada, Y. Yanai, T. Okazaki, N. Noma, I. Kawashima, T. Mori, and J. S. Richards (2008)
Development 135, 2001-2011
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882