Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4.
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 kappaB 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.
Chang
Eun-Ju
EJ
Department of Cell and Developmental Biology and Brain Korea 21 Program, DRI, Seoul National University, Seoul 110-749, Korea.
Kim
Hyon Jong
HJ
Ha
Jeongim
J
Kim
Hyung Joon
HJ
Ryu
Jiyoon
J
Park
Kwang-Hyun
KH
Kim
Uh-Hyun
UH
Lee
Zang Hee
ZH
Kim
Hyun-Man
HM
Fisher
David E
DE
Kim
Hong-Hee
HH
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
C476399:Cd44 protein, mouse; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D053246:Receptor Activator of Nuclear Factor-kappa B; C493487:Tlr4 protein, mouse; C505687:Tnfrsf11a protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D016173:Macrophage Colony-Stimulating Factor; D006820:Hyaluronic Acid