Monosodium Urate in the Presence of RANKL Promotes Osteoclast Formation through Activation of c-Jun N-Terminal Kinase.
The aim of this study was to clarify the role of monosodium urate (MSU) crystals in receptor activator of nuclear factor kB ligand- (RANKL-) RANK-induced osteoclast formation. RAW 264.7 murine macrophage cells were incubated with MSU crystals or RANKL and differentiated into osteoclast-like cells as confirmed by staining for tartrate-resistant acid phosphatase (TRAP) and actin ring, pit formation assay, and TRAP activity assay. MSU crystals in the presence of RANKL augmented osteoclast differentiation, with enhanced mRNA expression of NFATc1, cathepsin K, carbonic anhydrase II, and matrix metalloproteinase-9 (MMP-9), in comparison to RAW 264.7 macrophages incubated in the presence of RANKL alone. Treatment with both MSU crystals and RANKL induced osteoclast differentiation by activating downstream molecules in the RANKL-RANK pathway including tumor necrosis factor receptor-associated factor 6 (TRAF-6), JNK, c-Jun, and NFATc1. IL-1b produced in response to treatment with both MSU and RANKL is involved in osteoclast differentiation in part through the induction of TRAF-6 downstream of the IL-1b pathway. This study revealed that MSU crystals contribute to enhanced osteoclast formation through activation of RANKL-mediated pathways and recruitment of IL-1b. These findings suggest that MSU crystals might be a pathologic causative agent of bone destruction in gout.
Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea ; Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu 705-718, Republic of Korea.
Jung-Yoon
JY
Choe
Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu 705-718, Republic of Korea.
Ki-Yeun
KY
Park
Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea ; Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu 705-718, Republic of Korea.
Seong-Kyu
SK
Kim
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology*
D053583:Interleukin-1beta; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D014527:Uric Acid; D048031:JNK Mitogen-Activated Protein Kinases