Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C‐Terminal Crosslinking Telopeptide of Type II Collagen and N‐Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial

Struglics, A.; Larsson, S.; Kumahashi, Nobuyuki; Frobell, Richard; Lohmander, L. Stefan

doi:10.1002/art.39146

Cited by 92 publications

(180 citation statements)

References 51 publications

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“…The dramatic increase seen in the pro-inflammatory cytokine IL-6 over the control group is consistent with previous reports of subjects with acute knee injury and significantly higher than has been reported for OA SF [37, 38]. The lack of association of IL-6 with any of the other analytes is not unexpected since IL-6 is part of a generalized acute phase response to injury.…”

Section: Discussionsupporting

confidence: 90%

“…The use of SF from knees contralateral to diseased knees but which themselves exhibit minimal or no OA should closely approximate normal joints. Furthermore, the very low levels of IL-6 in this group were within the confidence interval of previous reports from normal SF controls and much lower than is seen in advanced OA, lending further credence to their use a control [37,38]. …”

Section: Discussionsupporting

confidence: 83%

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Xanthine oxidase injurious response in acute joint injury

Stäbler

Zura

Hsueh

et al. 2015

Clinica Chimica Acta

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Background While acute trauma is a major cause of osteoarthritis, its etiology is poorly understood. We sought to determine whether xanthine oxidase (XO), a major producer of reactive oxygen species, plays a role in the early events of acute joint injury. Methods We analyzed synovial fluid from 23 subjects with recent severe acute knee injury. As a control we evaluated SF from 23 individuals with no or minimal knee osteoarthritis. We measured XO activity, reactive oxygen+reactive nitrogen species (ROS+RNS), protein oxidative damage (carbonyl), the type II collagen synthesis marker procollagen II c-propeptide (CPII) and the type II collagen degradation marker collagen type II telopeptide (CTx-II). We also measured the proinflammatory cytokine IL-6. Results XO and ROS+RNS were higher (p=0.02 and p=0.001 respectively) in acute injury than control and were strongly positively associated (r=0.62, p=0.004). Carbonyl was higher in acute injury than control (p=0.0002) and was positively correlated with XO (r=0.68, p=0.0007) as well as with ROS+RNS (r=0.71, p=0.004). CPII was higher in acute injury than control (p<0.0001) and was negatively correlated with XO (r=−0.49, p=0.017). While CTxII was not significantly higher in acute injury than control, it was positively correlated with CPII (r=0.71, p=0.0002). IL-6 was higher in acute injury than control (p<0.0001). Conclusions These results are consistent with a potentially injurious effect of XO activity in acute joint injury characterized by excess free radical production and oxidative damage. These effects are associated with an inhibition of type II collagen production that may impede the ability of the injured joint to repair.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 83%

Xanthine oxidase injurious response in acute joint injury

Stäbler

Zura

Hsueh

et al. 2015

Clinica Chimica Acta

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“…Furman et al14 reported acute IM after an articular fracture, which was evidenced by increased synovitis, increased macrophage infiltration into the synovium, and increased concentration of biomarkers in the synovial fluid and serum. Chronicity of some of these phenomena, extending over 5 years, has been reported by Struglics 15. Our observations of the chronological sequence of RA development after trauma are well within this timeline.…”

Section: Discussionsupporting

confidence: 86%

The onset of rheumatoid arthritis following trauma

Brawer

Goel

2016

OARRR

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BackgroundRheumatoid arthritis (RA) is known to have many predisposing factors.ObjectiveWe studied individuals whose RA was initiated by physical injuries.Patients and methodsSixty patients (43 females), previously well, developed RA following trauma. No other known environmental or familial influences were present. Fourteen sustained a fracture; of the 46 who did not, 36 sustained multiple injuries that in part involved the axial skeleton. Subsequent unremitting daily pain, stiffness, limited motion, pain on motion, and/or swelling in the injured areas were mandatory for inclusion.ResultsNine months after injuries (span: 2 weeks–36 months), more obvious signs of inflammation (IM) appeared in multiple other joints that were previously not affected by the original trauma. In those with laboratory tests done prior to the spread of IM (30/60), 22 (73%) were normal until an average 8 months after the spread of IM. Of the entire cohort of 60, only 23% had a positive rheumatoid factor, but 43% had a positive antinuclear antibody.ConclusionIt seems apparent that any severe trauma to a joint may precipitate an ongoing localized chronic inflammatory disorder for an indefinite period of time, which may then lead to the spread of IM to multiple other joints. The initiation of RA following trauma warrants consideration as a legitimate entity.

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“…In the acute phase of injury, impact forces applied over the knee joint in combination with hemarthrosis lead to activation and recruitment of immune cells to the knee joint, producing an inflammatory and procatabolic joint environment. Several reports have demonstrated rapid increases in pro- and anti-inflammatory cytokines, proteases, and proteolytic activity after a severe knee injury [15–22]. Cells of the synovium and fibrous joint capsule (referred to hereafter as the synovium + joint capsule [SJC]), comprising resident inflammatory cells, synovial cells, and other cells such as endothelial cells and blood leukocytes, contribute to joint inflammation by producing proinflammatory mediators and proteases such as aggrecanases and MMPs [23, 24].…”

Section: Introductionmentioning

confidence: 99%

Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity

et al. 2017

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BackgroundA hallmark of osteoarthritis is increased proteolytic cleavage of aggrecan. Cross talk between cartilage and the synovium + joint capsule (SJC) can drive cartilage degradation by activating proteases in both tissues. We investigated aggrecan proteolysis patterns in cartilage explants using a physiologically relevant explant model of joint injury combining cartilage mechanical compression and coincubation with SJC.MethodsBovine cartilage explants were untreated; coincubated with SJC; or subjected to mechanical injury and coincubated with SJC, mechanical injury alone, or mechanical injury and incubated with tumor necrosis factor-α (TNF-α). To compare the patterns of aggrecan proteolysis between 6 h and 16 days, release of sulfated glycosaminoglycans and specific proteolytic aggrecan fragments into medium or remaining in cartilage explants was measured by dimethylmethylene blue and Western blot analysis.ResultsAggrecanase activity toward aggrecan was observed in all conditions, but it was directed toward the TEGE↓ARGS interglobular domain (IGD) site only when cartilage was coincubated with SJC or TNF-α. Matrix metalloproteinase (MMP) activity at the aggrecan IGD site (IPES↓FFGV) was not detected when cartilage was exposed to TNF-α (up to 6 days), but it was in all other conditions. Compared with when bovine cartilage was left untreated or subjected to mechanical injury alone, additional aggrecan fragment types were released into medium and proteolysis of aggrecan started at an earlier time when SJC was present.ConclusionsIndicative of different proteolytic pathways for aggrecan degradation, the SJC increases both aggrecanase and MMP activity toward aggrecan, whereas TNF-α inhibits MMP activity against the IGD of aggrecan.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1318-9) contains supplementary material, which is available to authorized users.

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Cited by 92 publications

References 51 publications

Xanthine oxidase injurious response in acute joint injury

Xanthine oxidase injurious response in acute joint injury

The onset of rheumatoid arthritis following trauma

Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity

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