The alarmins high mobility group box protein 1 and S100A8/A9 display different inflammatory profiles after acute knee injury.

OBJECTIVE: To compare the concentrations of high mobility group box 1 protein (HMGB1) and S100A8/A9 in synovial fluid between patients with knee injuries and osteoarthritis (OA), and knee healthy subjects. To investigate associations of alarmin levels with different joint injuries and with biomarkers of inflammation, Wnt signaling, complement system, bone and cartilage degradation. METHODS: HMGB1 and S100A8/A9 were measured in synovial fluid by immunoassays in patients with knee injuries, with OA and from knee healthy subjects, and were related to time from injury and with biomarkers obtained from previous studies. Hierarchical cluster and enrichment analyses of biomarkers associated to HMGB1 and S100A8/A9 were performed. RESULTS: The synovial fluid HMGB1 and S100A8/A9 concentrations were increased early after knee injury; S100A8/A9 levels were negatively associated to time after injury and was lower in the old compared to recent injury group, while HMGB1 was not associated to time after injury. The S100A8/A9 levels were also increased in OA. The initial inflammatory response was similar between the alarmins, and HMGB1 and S100A8/A9 shared 9 out of 20 enriched pathways. The alarmins displayed distinct response profiles, HMGB1 being associated to cartilage biomarkers while S100A8/A9 was associated to proinflammatory cytokines. CONCLUSIONS: HMGB1 and S100A8/A9 are increased as an immediate response to knee trauma. While they share many features in inflammatory and immunoregulatory mechanisms, S100A8/A9 and HMGB1 are associated to different downstream responses, which may have impact on the OA progression after acute knee injuries.

Changes in synovial fluid and serum concentrations of cartilage oligomeric matrix protein over 5 years after anterior cruciate ligament rupture: an exploratory analysis in the KANON trial.

OBJECTIVE: To monitor longitudinal changes of cartilage oligomeric matrix protein (COMP) in synovial fluid (sf) and serum (s) over 5 years after acute anterior cruciate ligament (ACL) rupture, and to compare results from two commercial COMP immunoassays. DESIGN: Bio-fluids were collected from 121 patients on six occasions over 5 years after acute ACL injury, and from 25 knee healthy reference subjects. Concentrations of sf- and sCOMP were measured by AnaMar (sCOMP-Ana) and by BioVendor (sf- and sCOMP-Bio) immunoassays; other biomarkers were previously assessed. We used ANCOVA for group comparisons and linear mixed models for associations between biomarkers over 5-years with P < 0.05 considered a statistically significant difference or association. RESULTS: Compared to the reference group, sfCOMP-Bio concentrations were 2-fold elevated within 6 weeks after ACL injury and remained elevated 5 years thereafter, whereas sCOMP-Bio and sCOMP-Ana concentrations were no different from reference levels at any time point. Over the 5-year period, there was an association between sCOMP-Bio and sCOMP-Ana concentrations, although neither sCOMP-Bio nor sCOMP-Ana associated with sfCOMP-Bio. sfCOMP-Bio associated with SF ARGS-aggrecan, urine type I and II collagens (uNTX-I and uCTX-II) and SF cytokines, while sCOMP-Bio associated inversely with uCTX-II, uNTX-I and SF cytokines. CONCLUSION: The local process after an acute ACL injury generates increased SF COMP concentrations in the injured knee up to 5 years after injury. This response is not detected in serum. Discrepancies in associations between sCOMP measured by BioVendor and AnaMar immunoassays with other biomarkers indicate differences in detected COMP fragments.

Type II collagen C2C epitope in human synovial fluid and serum after knee injury--associations with molecular and structural markers of injury.

PURPOSE: Investigate in a cross-sectional study time-dependent changes of synovial fluid type II collagen epitope C2C concentrations after knee injury and correlate to other joint injury biomarkers. METHODS: Synovial fluid samples were aspirated between 0 days and 7 years after injury (n = 235). Serum was collected from 71 of the knee injured patients. Synovial fluid from 8 knee-healthy subjects was used as reference. C2C was quantified by immunoassay and structural injury was determined from magnetic resonance images (MRI) of the injured knee acquired 1-38 days after injury (n = 98). Additional joint injury biomarker results were from earlier investigations of the same samples. RESULTS: Synovial fluid C2C concentrations were higher in injured knees than in knees of reference subjects from 1 day up to 7 years after injury. C2C concentrations in synovial fluid and serum were correlated (r = 0.403, P < 0.001). In synovial fluid from subjects early after injury (0-33 days), C2C concentrations were correlated with cross-linked C-telopeptide of type II collagen (r = 0.444, P = 0.003), ARGS-aggrecan (r = 0.337, P < 0.001), osteocalcin (r = 0.345, P < 0.001), osteopontin (r = 0.371, P < 0.001) and IL-8 (r = -0.385, P < 0.001), but not with structural joint injury as visualized on MRI. CONCLUSION: The increased levels of synovial fluid C2C after injury, together with the associations seen with several other injury-related biomarkers, suggest that an acute knee injury is associated with an immediate and sustained local degradation of type II collagen.

Imaging following acute knee trauma.

Joint injury has been recognized as a potent risk factor for the onset of osteoarthritis. The vast majority of studies using imaging technology for longitudinal assessment of patients following joint injury have focused on the injured knee joint, specifically in patients with anterior cruciate ligament injury and meniscus tears where a high risk for rapid onset of post-traumatic osteoarthritis is well known. Although there are many imaging modalities under constant development, magnetic resonance (MR) imaging is the most important instrument for longitudinal monitoring after joint injury. MR imaging is sensitive for detecting early cartilage degeneration and can evaluate other joint structures including the menisci, bone marrow, tendons, and ligaments which can be sources of pain following acute injury. In this review, focusing on imaging following acute knee trauma, several studies were identified with promising short-term results of osseous and soft tissue changes after joint injury. However, studies connecting these promising short-term results to the development of osteoarthritis were limited which is likely due to the long follow-up periods needed to document the radiographic and clinical onset of the disease. Thus, it is recommended that additional high quality longitudinal studies with extended follow-up periods be performed to further investigate the long-term consequences of the early osseous and soft tissue changes identified on MR imaging after acute knee trauma.

Cartilage and bone markers and inflammatory cytokines are increased in synovial fluid in the acute phase of knee injury (hemarthrosis)--a cross-sectional analysis.

PURPOSE: The aim of this cross-sectional study was to investigate concentrations of cartilage and bone markers, and pro-inflammatory cytokines in synovial fluid (SF) collected at different time-points from acutely injured knees with hemarthrosis and to compare these with SF concentrations of knees of age and gender-matched healthy reference subjects. METHODS: SF was aspirated from the acutely injured knee of 111 individuals (mean age 27 years, span 13-64 years, 22% women). Concentrations of sulfated glycosaminoglycan (sGAG) were measured by Alcian blue precipitation whereas cartilage ARGS, bone biomarkers [osteocalcin (OCL), secreted protein acidic and rich in cysteine (SPARC) and osteopontin (OPN)] and pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, IL-8 and tumor necrosis factor (TNF)-α] were analyzed using electrochemiluminescence. Samples were also analyzed with regard to time between injury and aspiration [same day (n = 29), 1 day (n = 31), 2-3 days (n = 19), 4-7 days (n = 20) and 8-23 days (n = 12)]. RESULTS: SF concentrations of ARGS (P < 0.001), SPARC (P < 0.001), OPN (P < 0.001), and all cytokines (P < 0.001), but not sGAG (P = 0.06) or OCL (P = 0.992), were significantly higher in injured knees compared to knees of reference subjects. The cartilage markers sGAG and ARGS were significantly higher in knees aspirated later than 1 day after injury, whereas concentrations of SPARC and OPN and all cytokines were higher in knees aspirated the same day as the injury and at all time-points thereafter. CONCLUSIONS: Our results suggest that an acute knee injury is associated with an instant local biochemical response to the trauma, which may affect cartilage and bone as well as the inflammatory activity.

Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability.

Microalbuminuria is an established marker of systemic endothelial dysfunction, which for patients with diabetes signals an increased risk of both diabetic nephropathy and cardiovascular complications. A better understanding of the pathogenesis of microalbuminuria is important in the quest of finding new approaches to treat patients with diabetes. Direct acute effects of episodes of hyperglycaemia (HG) could have implications for the microalbuminuria seen in early diabetes before renal structural alterations have started, especially in those patients with poor glycaemic control. This review summarizes the literature evidence that acute or sustained HG may lead to an increased vascular or glomerular permeability. Special focus is on glomerular barrier permeability. There is evidence in the literature that HG increases systemic capillary and glomerular barrier permeability within 20-30 min in vivo in rats and mice. Furthermore, exposure of monolayers of cultured endothelial cells to HG has been shown to increase monolayer permeability rapidly and transiently (during 60-100 min). Instant cellular changes following F-actin cytoskeleton rearrangements, which could be abrogated by Rho-kinase (ROCK) inhibition, are implicated. Data in this review also suggest that activation of protein kinase C, the polyol pathway, and an increased release of reactive oxygen species (ROS) and cytokines could contribute to the increase in barrier permeability induced by HG. Recent in vitro data from cultured podocyte monolayers also designates a role of insulin in acute podocyte F-actin remodelling, underpinning the complexity of the mechanisms leading to glomerular and endothelial barrier alterations in diabetes mellitus.

Differences in the radiological characteristics between post-traumatic and non-traumatic knee osteoarthritis.

Osteoarthritis (OA) of the knee can be defined as primary (non-traumatic) or secondary (post-traumatic). Both non-traumatic OA and post-traumatic OA have been described predominantly in the medial compartment of the knee. The objective of this study was to compare the location of structural radiographic changes in non-traumatic OA and post-traumatic OA. A non-traumatic cohort, consisting of 155 patients suffering from chronic knee pain without known major injuries, was compared with a post-traumatic cohort, consisting of 176 patients, all of whom had sustained an anterior cruciate ligament injury while playing soccer. A standardized weight-bearing knee radiography of the tibiofemoral joint was performed. Joint space narrowing (JSN) and osteophytes were graded according to the radiographic atlas of the Osteoarthritis Research Society International. JSN and osteophytes were located predominantly in the medial compartment in the non-traumatic cohort. In the post-traumatic cohort, structural changes were evenly distributed between the lateral and the medial compartments. We were thus able to demonstrate radiological differences between post-traumatic and non-traumatic OA.