Reciprocal cross-talk between RANKL and interferon-γ–inducible protein 10 is responsible for bone-erosive experimental arthritis

Kim²,

Kim³

et al. 2012

Cancer Research

Self Cite

Amplification of the chemokines CXCL10 and RANKL has been suggested to promote osteoclast differentiation and osteolytic bone metastasis, but a function for endogenous CXCL10 in these processes is not well established. In this study, we show that endogenous CXCL10 is critical to recruit cancer cells to bone, support osteoclast differentiation and promote for the formation of osteolytic bone metastases. Neutralizing CXCL10 antibody reduced migration of cancer cells expressing the CXCL10 receptor CXCR3, and loss of CXCR3 or CXCL10 decreased bone tumor burden in vivo. Bone colonization augmented host production of CXCL10, which was required for cancer growth and subsequent osteolysis. Direct interactions between cancer cells and macrophages further stimulated CXCL10 production from macrophages. Growth of bone metastases required CXCL10-stimulated adhesion of cancer cells to type I collagen as well as RANKL-mediated osteoclast formation. Together, our findings show that CXCL10 facilitates trafficking of CXCR3-expressing cancer cells to bone, which augments its own production and promotes osteoclastic differentiation. CXCL10 therefore may represent a therapeutic target for osteolytic bone metastasis. Cancer Res; 72(13); 3175-86. Ó2012 AACR.

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 61%

CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis

Kim²,

Kim³

et al. 2012

Cancer Research

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“…Although the role of IP-10 in periodontal disease has not been elucidated, accumulating data suggest a role for IP-10 in chronic inflammatory diseases, including arthritis and atherosclerosis. IP-10 has been reported to recruit inflammatory cells into inflamed joints and cause bone destruction, leading to arthritis in a mouse model (40). IP-10 deficiency significantly reduced early lesion formation in the aorta of ApoE Ϫ/Ϫ mice through modulation of both effector and regulatory T cells (41).…”

Section: Discussionmentioning

confidence: 99%

The Major Outer Membrane Protein of a Periodontopathogen Induces IFN-β and IFN-Stimulated Genes in Monocytes via Lipid Raft and TANK-Binding Kinase 1/IFN Regulatory Factor-3

The Journal of Immunology

Kim²,

Jun³

et al. 2009

Surface molecules of pathogens play an important role in stimulating host immune responses. Elucidation of the signaling pathways activated by critical surface molecules in host cells provides insight into the molecular pathogenesis resulting from bacteria-host interactions. MspTL is the most abundant outer membrane protein of Treponema lecithinolyticum, which is associated with periodontitis, and induces expression of a variety of proinflammatory factors. Although bacteria and bacterial components like LPS and flagellin are known to induce IFN-β, induction by bacterial surface proteins has not been reported. In the present study, we investigated MspTL-mediated activation of signaling pathways stimulating up-regulation of IFN-β and IFN-stimulated genes in a human monocytic cell line, THP-1 cells, and primary cultured human gingival fibroblasts. MspTL treatment of the cells induced IFN-β and the IFN-stimulated genes IFN-γ-inducible protein-10 (IP-10) and RANTES. A neutralizing anti-IFN-β Ab significantly reduced the expression of IP-10 and RANTES, as well as STAT-1 activation, which was also induced by MspTL. Experiments using specific small interfering RNA showed that MspTL activated TANK-binding kinase 1 (TBK1), but not inducible IκB kinase (IKKi). MspTL also induced dimerization of IFN regulatory factor-3 (IRF-3) and translocation into the nucleus. The lipid rapid-disrupting agents methyl-β-cyclodextrin, nystatin, and filipin inhibited the MspTL internalization and cellular responses, demonstrating that lipid raft activation was a prerequisite for MspTL cellular signaling. Our results demonstrate that MspTL, the major outer protein of T. lecithinolyticum, induced IFN-β expression and subsequent up-regulation of IP-10 and RANTES via TBK1/IRF-3/STAT-1 signaling secondary to lipid raft activation.

“…RANKL induces the expression of C-C chemokines such as CCL2, CCL3, CCL5, and CCL9, and C-X-C chemokines, such as CXCL10 (4)(5)(6)(7). CCL2/MCP-1, and CCL5/RANTES, induced by RANKL in human OCs, could promote the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated OCs without RANKL (4).…”

mentioning

confidence: 99%

CXC Chemokine Ligand 2 Induced by Receptor Activator of NF-κB Ligand Enhances Osteoclastogenesis

Choi

The Journal of Immunology

et al. 2010

Self Cite

CXCL2 has been known to regulate immune functions mainly by chemo-attracting neutrophils. In this study, we show that CXCL2 can be induced by receptor activator of NF-κB ligand, the osteoclast (OC) differentiation factor, through JNK and NF-κB signaling pathways in OC precursor cells. CXCL2 in turn enhanced the proliferation of OC precursor cells of bone marrow-derived macrophages (BMMs) through the activation of ERK. Knockdown of CXCL2 inhibited both the proliferation of and the ERK activation in BMMs. During osteoclastogenesis CXCL2 stimulated the adhesion and the migration of BMMs. Moreover, the formation of OCs from BMMs was significantly increased on treatment with CXCL2. Conversely, the CXCL2 antagonist repertaxin and a CXCL2 neutralizing Ab potently reduced receptor activator of NF-κB ligand-induced osteoclastogenesis. Furthermore, CXCL2 evoked fulminant bone erosion in the in vivo mouse experiments. Finally, prominent upregulation of CXCL2 was detected in synovial fluids and sera from rheumatoid arthritis patients, suggesting a potential involvement of CXCL2-mediated osteoclastogenesis in rheumatoid arthritis-associated bone destruction. Thus, CXCL2 is a novel therapeutic target for inflammatory bone destructive diseases.