C5aR1 interacts with <scp>TLR</scp>2 in osteoblasts and stimulates the osteoclast‐inducing chemokine <scp>CXCL</scp>10

Mödinger, Yvonne; Rapp, Anna E.; Pázmándi, Júlia; Vikman, Anna; Holzmann, Karlheinz; Haffner‐Luntzer, Melanie; Huber‐Lang, Markus; Ignatius, Anita

doi:10.1111/jcmm.13873

Cited by 29 publications

(18 citation statements)

References 65 publications

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“…We found 737 significantly downregulated genes in the AB uninjured group compared to the VEH uninjured group. These genes included regulators of skeletal development ( Alpl [ 37 ], Col6a1 [ 54 ], Col6a2 [ 55 ], Sox9 [ 37 ], Sox11 [ 56 ], and Wnt9a [ 57 ]), Hippo signaling ( Tead1 , Tead4 [ 58 ], and Yap1 [ 59 ]), muscle contraction ( Myh8 , Myh2 , and Myom2 ), and inflammatory response ( Tlr5 [ 60 ], Ccl8 [ 61 ], Cxcl13 [ 37 ], C5ar1 [ 62 ], Cxcr1 [ 63 ], and Foxo6 [ 64 ]). Inflammatory gene comparison between AB injured and uninjured groups compared to the corresponding VEH groups are shown in Figure 5 A and Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

Mendez

Murugesh

Sebastian

et al. 2020

IJMS

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Osteoarthritis (OA) is a painful and debilitating disease characterized by the chronic and progressive degradation of articular cartilage. Post-traumatic OA (PTOA) is a secondary form of OA that develops in ~50% of cases of severe articular injury. Inflammation and re-occurring injury have been implicated as contributing to the progression of PTOA after the initial injury. However, there is very little known about external factors prior to injury that could affect the risk of PTOA development. To examine how the gut microbiome affects PTOA development we used a chronic antibiotic treatment regimen starting at weaning for six weeks prior to ACL rupture, in mice. A six-weeks post-injury histological examination showed more robust cartilage staining on the antibiotic (AB)-treated mice than the untreated controls (VEH), suggesting slower disease progression in AB cohorts. Injured joints also showed an increase in the presence of anti-inflammatory M2 macrophages in the AB group. Molecularly, the phenotype correlated with a significantly lower expression of inflammatory genes Tlr5, Ccl8, Cxcl13, and Foxo6 in the injured joints of AB-treated animals. Our results indicate that a reduced state of inflammation at the time of injury and a lower expression of Wnt signaling modulatory protein, Rspo1, caused by AB treatment can slow down or improve PTOA outcomes.

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Section: Resultsmentioning

confidence: 99%

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

Mendez

Murugesh

Sebastian

et al. 2020

IJMS

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“…Another indirect mechanism by which TLRs can stimulate osteoclastogenesis is through TLR2-induced upregulation of the chemokine CXCL10 (104). Stimulation of mouse calvarial osteoblasts with Pam3 results in increased mRNA expression of Cxcl10 and CXCL10 protein.…”

Section: Tlr Activation Induces Osteoclastogenesis In Rankl-primed Cellsmentioning

confidence: 99%

Finding a Toll on the Route: The Fate of Osteoclast Progenitors After Toll-Like Receptor Activation

Souza

Lerner

2019

Front. Immunol.

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M-CSF and RANKL are two crucial cytokines stimulating differentiation of mature, bone resorbing, multinucleated osteoclasts from mononucleated progenitor cells in the monocyte/macrophage lineage. In addition to the receptors for M-CSF and RANKL, osteoclast progenitor cells express receptors for several other pro- and anti-osteoclastogenic cytokines, which also regulate osteoclast formation by affecting signaling downstream M-CSF and RANKL receptors. Similar to many other cells originating from myeloid hematopoetic stem cells, also osteoclast progenitors express toll-like receptors (TLRs). Nine murine TLRs are expressed in the progenitors and all, with the exception of TLR2 and TLR4, are downregulated during osteoclastogenesis. Activation of TLR2, TLR4, and TLR9, but not TLR5, in osteoclast progenitors stimulated with M-CSF and RANKL arrests differentiation along the osteoclastic lineage and keeps the cells at a macrophage stage. When the progenitors are primed with M-CSF/RANKL and then stimulated with agonists for TLR2, TLR4, or TLR9 in the presence of M-CSF, but in the absence of RANKL, the cells differentiate to mature, bone resorbing osteoclasts. TLR 2, 4, 5, and 9 are also expressed on osteoblasts and their activation increases osteoclast differentiation by an indirect mechanism through stimulation of RANKL. In mice, treatment with agonists for TLR2, 4, and 5 results in osteoclast formation and extensive bone loss. It remains to be shown the relative importance of inhibitory and stimulatory effects by TLRs on osteoclast progenitors and the role of RANKL produced by TLR stimulated osteoblasts, for the bone resorbing effects in vivo .

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“… 29 C5AR1 signaling in osteoblasts plays a detrimental role in bone regeneration by interacting with TLR2 and stimulating CXCL10. 28 The expression of HCAR2 in peripheral blood mononuclear cells was significantly lower in nonunion patients than in those with healed long bone fractures, thus acting as a valuable biomarker for nonunion diagnosis. 35 Tian and his colleagues demonstrated that C3AR1 might participate in the osteocyte apoptosis induced by myeloma cells.…”

Section: Discussionmentioning

confidence: 96%

“… 15 Importantly, large numbers of DEGs identified between the UHMWPE group and the VE-UHMWPE group also serve regulatory roles in osteoclastogenesis and bone resorption. 15 , 28 Some inflammatory diseases are associated with increased bone resorption and fracture rates because inflammatory cytokines produced by innate and adaptive immune cells could not only facilitate inflammation but also activate bone degeneration and inhibit bone formation. 29 The degree of inflammation is related to the extent of local and systemic bone loss.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Candidate Genes Related to Inflammatory Osteolysis Associated with Vitamin E-Blended UHMWPE Debris of Orthopedic Implants by Integrated Bioinformatics Analysis and Experimental Confirmation

Liu¹,

Dong²,

Zhou³

et al. 2021

JIR

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Purpose This study aims to identify differentially expressed genes (DEGs) in macrophages exposed to ultra-high-molecular-weight polyethylene (UHMWPE) or vitamin E-blended UHMWPE (VE-UHMWPE) particles, thereby providing potential targets for the treatment of inflammatory osteolysis. Methods The GSE104589 dataset of genome expression in macrophages exposed to UHMWPE and VE-UHMWPE was downloaded from the Gene Expression Omnibus database to identify DEGs. Functional enrichment analysis was performed using DAVID, and the corresponding protein–protein interaction (PPI) network was constructed from the STRING database. Important modules were selected using the molecular complex detection algorithm, and hub genes were identified in cytoHubba. MicroRNAs targeting these DEGs were obtained from the TarBase, miRTarBase, and miRecords databases, while transcription factors (TFs) targeting DEGs were predicted from the ENCODE database. Finally, the top five DEGs were validated by quantitative real‐time polymerase chain reaction (qRT-PCR). Results A total of 112 DEGs (44 upregulated and 68 downregulated DEGs) were screened. Immune and inflammatory responses were significantly related in gene ontology analysis, and 18 signaling pathways were enriched according to Kyoto Encyclopedia of Genes and Genomes pathway analysis. The PPI network involving 85 nodes and 266 protein pairs indicated that IL1β, CXCL1, ICAM1, CCL5 and CCL4 showed higher degrees. qRT-PCR analysis of the top five DEGs revealed a decreasing trend in the VE-UHMWPE group compared with the UHMWPE group. Key microRNAs (hsa-miR-144, hsa-miR-21, and hsa-miR-221) and TFs (RELA and NFKB1) were predicted to be correlated with the pathogenesis of inflammatory osteolysis through microRNA-TF regulatory network analysis. Conclusion The present study helps shed light on the molecular mechanisms underlying the changes in the wear-induced inflammatory process after blending vitamin E with UHMWPE. Hub genes including IL1β, CXCL1, ICAM1, CCL5, and CCL4, key microRNAs (hsa-miR-144, hsa-miR-21, and hsa-miR-221) and TFs (RELA and NFKB1) may serve as prognostic and therapeutic targets of inflammatory osteolysis.

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C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast‐inducing chemokine CXCL10

Cited by 29 publications

References 65 publications

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

Finding a Toll on the Route: The Fate of Osteoclast Progenitors After Toll-Like Receptor Activation

Identification of Key Candidate Genes Related to Inflammatory Osteolysis Associated with Vitamin E-Blended UHMWPE Debris of Orthopedic Implants by Integrated Bioinformatics Analysis and Experimental Confirmation

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