MKK3/6-p38 MAPK Signaling Is Required for IL-1<i>β</i> and TNF-<i>α</i>-Induced RANKL Expression in Bone Marrow Stromal Cells

Rossa, Carlos; Ehmann, Kathryn; Liu, Min; Patil, Chetan S.; Kirkwood, Keith L.

doi:10.1089/jir.2006.26.719

Cited by 66 publications

(72 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the involvement of JNK may not be necessarily be excluded, under the present indications the p38 MAPK pathway was further investigated in relation to the regulation of RANKL, OPG and COX-2 expression. Previous studies have shown that this pathway can directly or indirectly regulate inflammatory regulators, such as IL-1β, TNF-α, RANKL and PGE 2 [25,27,31].…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that MAPKs are implicated in RANKL, OPG and cyclooxygenase (COX)-2 regulation [23][24][25][26][27], and that MAPK signalling cascades can be activated in response to P. gingivalis infection [13,28]. Although previous works investigated the regulation of MAPKs in response to P. gingivalis, or the effects of P. gingivalis on RANKL, OPG and COX-2 expression, the putative cross-talks of these regulatory pathways are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Reddi

Brown

Belibasakis

2011

Microbial Pathogenesis

View full text Add to dashboard Cite

Periodontitis is a bacterially-induced oral inflammatory disease that is characterised by tissue degradation and bone loss. Porphyromonas gingivalis is a gram negative bacterial species highly associated with the pathogenesis of chronic periodontitis. Receptor activator of nuclear factor-kB ligand (RANKL) induces bone resorption whilst osteoprotegerin (OPG) is a decoy receptor that blocks this process. Cyclooxygenase-2 (COX-2) is an enzyme responsible for the production of prostaglandin (PGE)(2,) which is a major inflammatory mediator of bone resorption. Mitogen-activated protein kinases (MAPK) are intracellular signalling molecules involved in various cell processes, including inflammation. This study aimed to investigate the effect of P. gingivalis on MAPKs and their involvement in the regulation of RANKL, OPG and COX-2 expression in bone marrow stromal cells. P. gingivalis challenge resulted in the phosphorylation of primarily the p38 MAPK. RANKL and COX-2 mRNA expressions were upregulated, whereas OPG was down-regulated by P. gingivalis. The p38 synthetic inhibitor SB203580 abolished the P. gingivalis-induced RANKL and COX-2 expression, but did not affect OPG. Collectively, these results suggest that the p38 MAPK pathway is involved in the induction of RANKL and COX-2 by P. gingivalis, providing further insights into the pathogenic mechanisms of periodontitis. AbstractPeriodontitis is a bacterially-induced oral inflammatory disease that is characterised by tissue degradation and bone loss. Porphyromonas gingivalis is a gram negative bacterial species highly associated with the pathogenesis of chronic periodontitis. Receptor activator of nuclear factor-kB ligand (RANKL) induces bone resorption whilst osteoprotegerin (OPG) is a decoy receptor that blocks this process. Cyclooxygenase-2 (COX-2) is an enzyme responsible for the production of prostaglandin (PGE) 2, which is a major inflammatory mediator of bone resorption. Mitogen-activated protein kinases (MAPK) are intracellular signalling molecules involved in various cell processes, including inflammation. This study aimed to investigate the effect of P. gingivalis on MAPKs and their involvement in the regulation of RANKL, OPG and COX-2 expression in bone marrow stromal cells. P. gingivalis challenge resulted in the phosphorylation of primarily the p38 MAPK. RANKL and COX-2 mRNA expressions were up-regulated, whereas OPG was down-regulated by P. gingivalis. The p38 synthetic inhibitor SB203580 abolished the P. gingivalis-induced RANKL and COX-2 expression, but did not affect OPG. Collectively, these results suggest that the p38 MAPK pathway is involved in the induction of RANKL and COX-2 by P. gingivalis, providing further insights into the pathogenic mechanisms of periodontitis. KeywordsPorphyromonas gingivalis, Bone marrow stromal cells, Receptor activator of nuclear factor-kB ligand, Osteoprotegerin, Cyclooxygenase -2, p38 MAPK.3

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Reddi

Brown

Belibasakis

2011

Microbial Pathogenesis

View full text Add to dashboard Cite

show abstract

“…NOR pretreatment for 24 h failed to alter TRAF6 expression (Figure 6), suggesting that the inhibition of cytokines expression by NOR might not be mediated through interfering with the initial signal. Effects of NOR on IL-1β-induced activation of JAK2/STAT3 and AKT in FLS from AIA rats It is widely accepted that MAPKs, JAK2/STAT3, and AKT, which are located downstream of the TRAF6 signaling complex, play important roles in the IL-1β-induced activation of FLS and the subsequent expressions of proinflammatory cytokines by triggering a cascade reaction [23][24][25][26] . In previous studies, we have demonstrated that NOR could significantly down-regulate the IL-1β-induced activation of p38 MAPK and ERK in FLS [10] .…”

Section: Resultsmentioning

confidence: 99%

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

et al. 2013

View full text Add to dashboard Cite

Aim: To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms. Methods: AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR. Results: In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE 2 , and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE 2 , and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE 2 , and MMP-13 proteins. Conclusion: NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE 2 , and MMP-13 expression via the p38/ERK/ AKT/AP-1 pathway.

show abstract

“…59,60 A phase II clinical trial was recently completed using a highly specific p38 MAP kinase inhibitor, SCIO-469 either alone or in combination with bortezomib. The results of this trial are not yet available.…”

Section: Other Novel Therapies For Myeloma Bone Diseasementioning

confidence: 99%

Treatment strategies for bone disease

Roodman

2007

Bone Marrow Transplant

View full text Add to dashboard Cite

Multiple myeloma is characterized by extensive bone destruction with little or no new bone formation. A multiplicity of factors including receptor activator NF-jB (RANKL), macrophage inflammatory protein-1a, interleukin-3 and interleukin-6 can induce osteoclast formation in myeloma and drive the bone destructive process. Furthermore, factors are also produced either in the microenvironment or by myeloma cells themselves, which inhibit osteoblast differentiation and new bone formation. The combination of increased osteoclast formation with little or no bone repair in response to the previous bone destruction explains the severity of the bone disease in myeloma. Studies of the pathophysiology of myeloma bone disease have identified several novel therapeutic targets. These include antibodies to RANKL, chemokine receptor antagonists, which block the effects of chemokines on osteoclast differentiation and proteasome antagonists, which can affect both RANKL production and osteoprotegerin levels as well as inhibit osteoclast and enhance osteoblast differentiation. In addition, many of the new biologic agents being used for the treatment of patients with myeloma also further inhibit the bone destructive process. New therapies that can target both the tumor as well as the severe bone disease should be on the horizon to treat this devastating complication of myeloma.

show abstract

MKK3/6-p38 MAPK Signaling Is Required for IL-1β and TNF-α-Induced RANKL Expression in Bone Marrow Stromal Cells

Cited by 66 publications

References 40 publications

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

Treatment strategies for bone disease

Contact Info

Product

Resources

About