Synovial fluid levels of bradykinin correlate with biochemical markers for cartilage degradation and inflammation in knee osteoarthritis

Bellucci, Francesco; Meini, Stefania; Cucchi, Paola; Catalani, Claudio; Nizzardo, Andrea; Riva, Alberto; Guidelli, Giacomo Maria; Ferrata, Paolo; Fioravanti, Antonella; Maggi, C.A.

doi:10.1016/j.joca.2013.08.014

Cited by 35 publications

(39 citation statements)

References 51 publications

(42 reference statements)

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“…Conversely, we did not observe a correlation between CGRP and pain intensity. Lastly, BK is an inflammatory mediator that can lead to vasodilation and inflammation induction, and SF levels of BK have been 14 reported to correlate with biochemical markers of cartilage degradation and inflammation in KOA (29). In our study, BK did not correlate with any pain score, a result that is consistent with previous findings.…”

Section: Discussionsupporting

confidence: 92%

Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis

Liu

et al. 2019

Preprint

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Background: Inflammatory mediators in the synovial fluid (SF) play critical roles in the initiation and development of pain in knee osteoarthritis (KOA). However, data for inflammatory marker expression are conflicting, and the role of SF inflammatory mediators in neuropathic pain is not clear. Therefore, the aim of this study was to identify SF inflammatory mediators associated with nociceptive and neuropathic pain in KOA. Methods: Levels of IL-1β, IL-6, TNF-α, macrophage colony-stimulating factor, MMP-3, MMP-13, metalloproteinase with thrombospondin motifs 5, calcitonin gene-related peptide, neuropeptide Y, substance P and bradykinin were measured using enzyme-linked immunosorbent assays in 86 patients. Nociceptive pain was assessed using the numeric rating scale (NRS), visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. Neuropathic pain was determined using the PainDETECT questionnaire. Moreover, knee function was evaluated by the WOMAC score and range of motion (ROM) assessments. Radiological grade was defined using the Kellgren-Lawrence (K-L) grading scale. Results: Pain scores measured using different methods correlated highly with each other. A worse K-L grade and knee function were associated with worse pain. Expression of IL-1β and IL-6 was increased in the early stage compared with the late stage. The NRS score correlated positively with age, K-L grade, and the WOMAC score and negatively with ROM and TNF-α expression. The VAS correlated positively with age, K-L grade, and the WOMAC score but negatively with ROM and levels of IL-1β, IL-6 and TNF-α. The WOMAC pain score did not correlate with any of the inflammatory mediators measured; it correlated only with ROM. The PainDETECT score correlated only with the WOMAC score. Expression of other inflammatory mediators did not correlate with any of the pain scores. Conclusions: IL-1β, IL-6 and TNF-α play critical roles in pain in the early stage of KOA and correlate with pain. The catabolic enzymes and neuropeptides measured do not correlate with nociceptive and neuropathic pain. New biomarkers related to pain in the late stage need to be further investigated.

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Section: Discussionsupporting

confidence: 92%

Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis

Liu

et al. 2019

Preprint

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“…13 Taken together, these data suggest that substance P may be an important regulator of catabolism of articular cartilage in OA. Bradykinin levels correlate with glycosoaminoglycan fragments in synovial fluid of OA patients, 56 which could suggest a link to matrix degradation. Bradykinin is also known for its ability to induce the activation of the ADAM17-EGFR transactivation pathway 57 …”

Section: Neurovascular Peptides and Metalloproteinase Expressionmentioning

confidence: 99%

Chondrocyte responses to neurovascular peptides, cytokines, and a 3D environment: focus on ADAMs

Bevan¹,

Baker²,

Goldring

et al. 2016

MNM

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Chondrocyte exposure to inflammatory stimuli in several arthritic conditions, including osteoarthritis, results in the well-characterized induction of extracellular matrix degrading proteinases, notably members of a disintegrin and metalloproteinase (ADAM) with thrombospondin domains and matrix metalloproteinase families. Here we briefly review the less-studied ADAM family of proteinases in chondrocyte and cartilage biology. Following damage, cartilage is exposed to neurovascular peptides, and in this study we hypothesized that substance P and bradykinin, alongside inflammatory cytokines, may modulate chondrocyte steady-state messenger RNA levels for the proteolytic ADAM family members as well as for key cytokines and neuropeptides. We compared chondrocytes cultured in both two-dimensional and three-dimensional (3D) environments and found that 3D culture generally resulted in repression of expression of the genes under investigation, with the exception of anti-inflammatory interleukin 10 which was markedly upregulated in a 3D environment. Substance P and bradykinin had little effect on ADAM family expression, but further investigation revealed that a combination of bradykinin and cytokines led to enhanced expression of ADAM28 and a synergistic upregulation of interleukin 6, also observed under hypoxic conditions. Overall these data reveal wider chondrocyte responses to neurovascular peptides which may have an impact in an osteoarthritis context.

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“…Bradykinin, a vasodilator and inflammatory nonapeptide, has been detected in the synovial fluid of OA patients and its levels correlate with the degree of synovitis [16,17]. BDKRB2 is present in human synovial tissues and in cultured human synoviocytes [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

Chen

Zhang

et al. 2016

Cell Physiol Biochem

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Background/Aims: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. Methods: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. Results: The presence of -9 bp genotype is associated with higher TNF-α, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. Conclusion: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression.

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Synovial fluid levels of bradykinin correlate with biochemical markers for cartilage degradation and inflammation in knee osteoarthritis

Abstract: The presence of BK in the knee OA SF and its correlations with cartilage degradation and inflammation markers of OA support its participation in OA pathology.

Cited by 35 publications

References 51 publications

Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis

Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis

Chondrocyte responses to neurovascular peptides, cytokines, and a 3D environment: focus on ADAMs

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

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