Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss

Yu, Hong; Li, Qiyan; Herbert, Bethany A.; Zinna, Robert A.; Martin, Kylie L.; Rossa, Carlos; Kirkwood, Keith L.

doi:10.1038/gt.2010.139

Cited by 50 publications

(80 citation statements)

References 36 publications

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“…MKP-1 (gene Dusp1 ), the family archetype, preferentially dephosphorylates phospho (p)-p38 and p-JNK [13]. With regard to oral bone loss, our group has demonstrated that alveolar bone loss is more pronounced in LPS-induced in mice lacking MKP-1 and that overexpression of MKP-1 protects from LPS-induced bone loss [14, 15]. Given the ability of MKP-1 to negatively regulate MAPK induced inflammatory cytokines in response to LPS, we hypothesized that bone loss was due to an exacerbated cytokine response within the periodontal microenvironment.…”

Section: Introductionmentioning

confidence: 99%

“…While CXCL2 has been shown to be involved in LPS-driven OCgen, the signaling mechanisms governing chemokines in OCgen remain to be defined [19]. In this study, we evaluated the role of MKP-1 in controlling OC-directed bone turnover in response to the periodontal pathogen A. actinomycetemcomitans LPS[15]. As a negative regulator of inflammatory MAPK pathways and subsequent cytokines/chemokines, we hypothesized that MKP-1 may control inflammatory driven OC formation through activity of the chemokine CXCL2.…”

Section: Introductionmentioning

confidence: 99%

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Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2

et al. 2015

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Osteoclast (OC) progenitors (OCP) have been defined in the bone marrow (BM) as CD3−CD45R(B220)−GR1−CD11blo/−CD115+ (dOCP) and more recently in the peripheral blood (PB) as Lym−Ly6G−CD11b+Ly6C+. These progenitors respond to stimuli, including LPS from periopathogenic Aggregatibacter actinomycetemcomitans, activating MAPK signaling, resulting in cytokine/chemokine-mediated osteoclastogenesis. Intracellular negative signaling pathways, including MAPK phosphatase-1 (MKP-1, gene Dusp1) deactivate MAPK pathways (p-p38 and p-JNK) and reduce inflammatory cytokines/chemokines. Objective To delineate the role of MKP-1 in chemokine-mediated OC formation using defined OC progenitor populations. Given its role in innate immune inflammatory signaling, we hypothesize that MKP-1 regulates LPS-induced OC formation from BM OCP through deregulated chemokines. Methods BM and PB from WT and Dusp1−/− female mice (8–12wks) was obtained and sorted into defined progenitor populations. BM sorted dOCP were primed with MCSF and RANKL (48hrs), blocked with vehicle or chemokine blocking antibodies and stimulated with LPS (48–96hrs). TRAP assay and OC activity were measured for OC formation and activity following treatments. Nanostring Array and qPCR were utilized for gene expression analysis. Results Dusp1−/− dOCPs formed more and larger osteoclasts from CD11bhi and dOCP compared to matched WT (P<0.05 each). PB-derived dOCP produced larger and more functional osteoclasts from Dusp1−/− mice compared to WT controls. Nanostring array data revealed significant deregulation in chemokine expression from Dusp1−/− vs. WT cells. qPCR validation of target genes revealed that Dusp1 deficient CD11b+ populations display 1.5–3.5-fold greater expression of CXCL1 and 2–3-fold greater expression of CXCL2 compared to WT in CD11bhi and dOCP (P<0.05 each). Antibody blocking studies using anti-CXCL1 and CXCL2 antibodies blunted osteoclastogenesis in Dusp1−/− cells. Conclusion MKP-1 negatively regulates chemokine-driven OC formation and subsequent bone resorption in response to LPS stimulation. Collectively, these data provide useful insight into mechanisms potentially leading to the development of therapeutic treatment of periodontal disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2

et al. 2015

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“…The Institutional Animal Care and Use Committee at the Medical University of South Carolina approved all experimental protocols. During the last 4 wk of regular chow or HFD feeding, 14 mice (7 fed regular chow and 7 fed a HFD) were injected with LPS (20 µg per mouse) isolated from A. actinomycetemcomitans (strain Y4, serotype B; Yu et al 2011) through both the left and right sides of the palatal gingiva between the maxillary first and second molars, 3 times per week as described previously (Rogers et al 2007;. For control, 14 mice (7 fed regular chow and 7 fed a HFD) were injected with phosphate-buffered saline (PBS), the vehicle for LPS.…”

Section: Animal Treatmentsmentioning

confidence: 99%

Metabolic Syndrome Exacerbates Inflammation and Bone Loss in Periodontitis

Zhang

et al. 2014

J Dent Res

111

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Clinical studies have shown that metabolic syndrome (MetS) is associated with increased risk of developing periodontitis. However, the underlying mechanisms remain largely unknown. Since it is known that lipopolysaccharide (LPS)-activated toll-like receptor 4 signaling pathways play a crucial role in periodontitis, we hypothesized that MetS enhances LPS-induced periodontal inflammation and alveolar bone loss. In this study, we induced MetS in C57BL/6 mice by feeding them high-fat diet (HFD), and we induced periodontitis by periodontal injection of Aggregatibacter actinomycetemcomitans LPS. We found that mice fed a HFD had significantly increased body weight, plasma lipids, insulin, and insulin resistance when compared with mice fed regular chow, indicating that the mice developed MetS. We also found that a HFD markedly increased LPSinduced alveolar bone loss, osteoclastogenesis, and inflammatory infiltration. Analysis of gene expression in periodontal tissue revealed that HFD and LPS injection cooperatively stimulated expression of cytokines that are known to be involved in periodontal tissue inflammation and osteoclastogenesis-such as interleukin 6, monocyte-chemotactic protein 1, receptor activator of nuclear factor kappa-B ligand, and macrophage colony-stimulating factor. To further understand the potential mechanisms involved in MetS-boosted tissue inflammation, our in vitro studies showed that palmitic acid-the most abundant saturated fatty acid (SFA) and the major SFA in the HFD used in our animal study-potently enhanced LPS-induced proinflammatory gene expression in macrophages. In sum, this study demonstrated that MetS was associated with increased periodontal inflammation and alveolar bone loss in an LPS-induced periodontitis animal model. This study also suggests that SFA palmitic acid may play an important role in MetS-associated periodontitis by enhancing LPS-induced expression of inflammatory cytokines in macrophages.

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“…Systemic transduction with TIMP-4 was reported to reduce both adjuvant-induced arthritis and periodontitis in rats (39). Inhibition of periodontal bone loss following AAV gene transfer of mitogen-activated protein kinase phosphatase-1 (MKP-1), which dephosphorylates MAPKs and inhibits immune responses, was also reported (40). Transduction of gingival tissues with AAV/2/1-tumor necrosis factor receptor-immunoglobulin FIG 6 AAV-sh-Atp6i reduced the expression of osteoclast marker genes and cytokines in periapical lesions.…”

Section: Discussionmentioning

confidence: 99%

RNA Interference-Mediated Silencing of Atp6i Prevents Both Periapical Bone Erosion and Inflammation in the Mouse Model of Endodontic Disease

Chen

Zhang³

et al. 2013

Infect Immun

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dDental caries is one of the most prevalent infectious diseases in the United States, affecting approximately 80% of children and the majority of adults. Dental caries may lead to endodontic disease, where the bacterial infection progresses to the root canal system of the tooth, leading to periapical inflammation, bone erosion, severe pain, and tooth loss. Periapical inflammation may also exacerbate inflammation in other parts of the body. Although conventional clinical therapies for this disease are successful in approximately 80% of cases, there is still an urgent need for increased efficacy of treatment. In this study, we applied a novel gene-therapeutic approach using recombinant adeno-associated virus (AAV)-mediated Atp6i RNA interference (RNAi) knockdown of Atp6i/TIRC7 gene expression to simultaneously target periapical bone resorption and periapical inflammation. We found that Atp6i inhibition impaired osteoclast function in vitro and in vivo and decreased the number of T cells in the periapical lesion. Notably, AAV-mediated Atp6i/TIRC7 knockdown gene therapy reduced bacterial infection-stimulated bone resorption by 80% in the mouse model of endodontic disease. Importantly, Atp6i؉/؊ mice with haploinsufficiency of Atp6i exhibited protection similar to that in mice with bacterial infection-stimulated bone erosion and periapical inflammation, which confirms the potential therapeutic effect of AAV-small hairpin RNA (shRNA)-Atp6i/TIRC7. Our results demonstrate that AAV-mediated Atp6i/TIRC7 knockdown in periapical tissues can inhibit endodontic disease development, bone resorption, and inflammation, indicating for the first time that this potential gene therapy may significantly improve the health of those who suffer from endodontic disease.

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Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss

Cited by 50 publications

References 36 publications

Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2

Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2

Metabolic Syndrome Exacerbates Inflammation and Bone Loss in Periodontitis

RNA Interference-Mediated Silencing of Atp6i Prevents Both Periapical Bone Erosion and Inflammation in the Mouse Model of Endodontic Disease

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