Bradykinin potentiates cytokine‐induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression

Brechter, Anna Bernhold; Lerner, Ulf H.

doi:10.1002/art.22445

Cited by 53 publications

(48 citation statements)

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“…It has been reported that BK stimulates the expression of COX-2 mRNA in calvarial bones (32). LPS may also induce the expression of iNOS and COX-2 in RAW264.7 macrophages (17).…”

Section: Discussionmentioning

confidence: 97%

N‑methyl pyrrolidone promotes ankle fracture healing by inhibiting inflammation via suppression of the mitogen‑activated protein kinase signaling pathway

et al. 2018

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Abstract. N-methyl pyrrolidone (NMP), a small bioactive molecule, has the potential to stimulate bone formation and inhibit osteoclast differentiation. The aim of the present study was to investigate the effect of NMP on the inflammatory response and underlying molecular mechanisms in MG-63 cells. The mRNA and protein expression of cytokines from peripheral blood in children with or without ankle fracture were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA, respectively. MG-63 cells were pre-treated with/without NMP and stimulated with 1 µM bradykinin (BK). The production of cytokines from MG-63 cells was assessed by western blotting and RT-qPCR. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein were measured using western blotting and/or RT-qPCR. Western blotting was used to examine the activation level of mitogen activated protein kinase. Compared with healthy children, levels of tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 mRNA and protein were upregulated in children with ankle fracture. NMP treatment did not induce cytotoxicity in MG-63 cells. The BK-induced upregulation of TNF-α, IL-1β, IL-6, iNOS and COX-2 mRNA and protein was reversed in a dose-dependent manner by NMP. Furthermore, NMP downregulated the activation of c-Jun NH2-terminal kinase and p38 pathways, but not the extracellular signal-related kinase pathway. Therefore, the results of the current study demonstrate that NMP inhibits inflammation dependent on the mitogen-activated protein kinase pathway in MG-63 cells, indicating that it may be beneficial in the healing of fractures.

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“…It has been reported that BK stimulates the expression of COX-2 mRNA in calvarial bones (32). LPS may also induce the expression of iNOS and COX-2 in RAW264.7 macrophages (17).…”

Section: Discussionmentioning

confidence: 97%

N‑methyl pyrrolidone promotes ankle fracture healing by inhibiting inflammation via suppression of the mitogen‑activated protein kinase signaling pathway

et al. 2018

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“…We find that lack of both bradykinin receptors results in a severe reduction in bone mineral density both in Akita diabetic and nondiabetic mice, demonstrating the importance of the KKS in bone mineralization. However, although osteoblasts express both B1R and B2R, their stimulation with bradykinin increases expression of the receptor activator for NF-κB ligand, which is known to be involved in osteoclastogenesis (49). This in vitro observation consequently suggests that acute stimulation of KKS can cause bone resorption.…”

Section: Discussionmentioning

confidence: 98%

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

Kakoki¹,

Sullivan

Backus

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

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An insertion polymorphism of the angiotensin-I converting enzyme gene (ACE) is common in humans and the higher expressing allele is associated with an increased risk of diabetic complications. The ACE polymorphism does not significantly affect blood pressure or angiotensin II levels, suggesting that the kallikrein-kinin system partly mediates the effects of the polymorphism. We have therefore explored the influence of lack of both bradykinin receptors (B1R and B2R) on diabetic nephropathy, neuropathy, and osteopathy in male mice heterozygous for the Akita diabetogenic mutation in the insulin 2 gene (Ins2). We find that all of the detrimental phenotypes observed in Akita diabetes are enhanced by lack of both B1R and B2R, including urinary albumin excretion, glomerulosclerosis, glomerular basement membrane thickening, mitochondrial DNA deletions, reduction of nerve conduction velocities and of heat sensation, and bone mineral loss. Absence of the bradykinin receptors also enhances the diabetes-associated increases in plasma thiobarbituric acid-reactive substances, mitochondrial DNA deletions, and renal expression of fibrogenic genes, including transforming growth factor beta1, connective tissue growth factor, and endothelin-1. Thus, lack of B1R and B2R exacerbates diabetic complications. The enhanced renal injury in diabetic mice caused by lack of B1R and B2R may be mediated by a combination of increases in oxidative stress, mitochondrial DNA damage and over expression of fibrogenic genes.diabetes mellitus complications | kinins T he angiotensin-I converting enzyme (ACE) is a dipeptidyl carboxypeptidase, named because it removes two amino acids from the carboxyl terminus of the inactive peptide angiotensin I and converts it into the active blood pressure-raising peptide, angiotensin II. However, ACE is also a kininase and converts the active vasodilatory kinins into inactive metabolites by removing two amino acids from their carboxyl termini (1). Prior experimental findings (2) and computer simulations (3) show that modest changes in ACE levels affect the levels of its substrates much more than its products, indicating that relatively small changes in the levels of ACE affect kinin levels more than angiotensin II levels.The common insertion/deletion (I/D) polymorphism of the ACE gene in humans is due to the presence or absence of an Alu retrotransposon in the 16th intron of the gene. The polymorphism is associated with up to a twofold difference in relative plasma ACE levels (4), but the polymorphism does not significantly affect blood pressure or angiotensin II or aldosterone levels (5). Nevertheless, the I and D human ACE alleles are associated with different risks for developing diabetic complications including nephropathy (6

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“…29 In this study, we found that bradykinin concentrations were increased during ramipril [35][36][37] and may enhance the effects of IL-1b. 38 On the other hand, IL-1b induces the expression of bradykinin receptors. 39 Inflammatory cytokines predict cardiovascular endpoints in ESRD patients.…”

Section: Discussionmentioning

confidence: 99%

Comparative Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin-Receptor Blockade on Inflammation during Hemodialysis

Gamboa¹,

Pretorius²,

Todd-Tzanetos³

et al. 2012

Journal of the American Society of Nephrology

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Biomarkers of oxidative stress and inflammation predict cardiovascular events in maintenance hemodialysis patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) reduce cardiovascular mortality in the general population, but their benefit in maintenance hemodialysis patients is not fully explored. To test whether ACE inhibitors and ARBs differentially affect markers of oxidative stress, inflammation, and fibrinolysis during hemodialysis, we conducted a randomized, doubleblind, placebo-controlled 333 crossover study. We randomly assigned 15 participants undergoing hemodialysis to placebo, ramipril (5 mg/d), and valsartan (160 mg/d) for 7 days, with a washout period of 3 weeks in between the treatments. On the morning of the seventh day of drug treatment, participants underwent serial blood sampling during hemodialysis. Neither ramipril nor valsartan affected BP during hemodialysis. Ramipril increased IL-1b concentrations (P=0.02) and decreased IL-10 concentrations (P=0.04) compared with placebo. Valsartan and ramipril both lowered IL-6 levels during dialysis (P,0.01 for each compared with placebo). Valsartan increased F 2 -isoprostane levels, and ramipril suggested a similar trend (P=0.09). Valsartan and ramipril both lowered D-dimer levels (P,0.01 for both), whereas only ramipril seemed to prevent a rise in vWf levels (P=0.04). In summary, during hemodialysis, valsartan induces a greater anti-inflammatory effect compared with ramipril, although ramipril seems to prevent dialysis-induced endothelial dysfunction as measured by levels of vWf. A prospective clinical trial is necessary to determine whether ACE inhibitors and ARBs also differ with respect to their effects on cardiovascular mortality in this population. 23: 334-342, 201223: 334-342, . doi: 10.1681 In ESRD patients, cardiovascular death accounts for .50% of overall mortality and the risk of cardiovascular death is 30 times higher than in the general population. 1,2 Moreover, patients undergoing maintenance hemodialysis (MHD) have a 5-year survival rate of 10% after acute myocardial infarction. 3 Traditional risk factors, as used in Framingham risk scoring, only explain half of the excessive cardiovascular mortality observed in ESRD patients, 4 and it is thought that other factors contribute to the high cardiovascular mortality among ESRD patients. J Am Soc NephrolIncreased oxidative stress and inflammation may contribute to accelerated atherosclerosis and cardiovascular events in patients with MHD. 5,6 Markers of oxidative stress, such as F 2 -isoprostanes, are increased in MHD patients. 7,8 Inflammatory markers, particularly IL-1, IL 6, and TNFa, are also elevated in MHD patients and are associated with

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Bradykinin potentiates cytokine‐induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression

Cited by 53 publications

References 50 publications

N‑methyl pyrrolidone promotes ankle fracture healing by inhibiting inflammation via suppression of the mitogen‑activated protein kinase signaling pathway

N‑methyl pyrrolidone promotes ankle fracture healing by inhibiting inflammation via suppression of the mitogen‑activated protein kinase signaling pathway

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

Comparative Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin-Receptor Blockade on Inflammation during Hemodialysis

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