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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}snu.ac.kr)

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

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