IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1).
Toll-like receptors (TLR) and the receptor for interleukin-1 (IL-1R) signaling play an important role in bacteria-mediated bone loss diseases including periodontitis, rheumatoid arthritis, and osteomyelitis. Recent studies have shown that TLR ligands inhibit the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation from un-committed osteoclast precursors, whereas IL-1 potentiates RANKL-induced osteoclast formation. However, IL-1R and TLR belong to the same IL-1R/TLR superfamily, and activate similar intracellular signaling pathways. Here, we investigate the molecular mechanisms underlying the distinct effects of IL-1 and Porphyromonas gingivalis lipopolysaccharide (LPS-PG) on RANKL-induced osteoclast formation. Our results show that LPS-PG and IL-1 differentially regulate RANKL-induced activation of osteoclast genes encoding Car2, Ctsk, MMP9, and TRAP, as well as expression of NFATc1, a master transcription factor of osteoclastogenesis. Regulation of osteoclast genes and NFATc1 by LPS-PG and IL-1 is dependent on MyD88, an important signaling adaptor for both TLR and IL-1R family members. Furthermore, LPS-PG and IL-1 differentially regulate RANKL-costimulatory receptor OSCAR (osteoclast-associated receptor) expression and Ca(2+) oscillations induced by RANKL. Moreover, LPS-PG completely abrogates RANKL-induced gene expression of B lymphocyte-induced maturation protein-1 (Blimp1), a global transcriptional repressor of anti-osteoclastogenic genes encoding Bcl6, IRF8, and MafB. However, IL-1 enhances RANKL-induced blimp1 gene expression but suppresses the gene expression of bcl6, irf8, and mafb. Our study reveals the involvement of multiple signaling molecules in the differential regulation of RANKL-induced osteoclastogenesis by TLR2 and IL-1 signaling. Understanding the signaling cross-talk among TLR, IL-1R, and RANK is critical for identifying therapeutic strategies to control bacteria-mediated bone loss.
From the Departments of Pediatric Dentistry, the Department of Prosthodontics, School and Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang 310006, China, and.
Zhihong
Z
Chen
From the Departments of Pediatric Dentistry.
Lingkai
L
Su
From the Departments of Pediatric Dentistry, the The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
Qingan
Q
Xu
From the Departments of Pediatric Dentistry.
Jenny
J
Katz
Microbiology, and.
Suzanne M
SM
Michalek
the The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
Mingwen
M
Fan
Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Xu
X
Feng
From the Departments of Pediatric Dentistry, pingz@uab.edu.
Ping
P
Zhang
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D053245:RANK Ligand / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D007375:Interleukin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C513258:Prdm1 protein, mouse; D053245:RANK Ligand; D017472:Receptors, Interleukin-1; C493486:Tlr2 protein, mouse; C505689:Tnfsf11 protein, mouse; D051195:Toll-Like Receptor 2; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
Porphyromonas gingivalis; Toll-like receptor (TLR); interleukin 1 (IL-1); lipopolysaccharide (LPS); myeloid differentiation primary response gene (88) (MYD88); osteoclast; receptor activator of NF-κB ligand (RANKL); signaling; transcription repressor