Serum Hyaluronan Concentration Research Articles

Development of Therapeutic Agent for Osteoarthritis via Inhibition of KIAA1199 Activity: Effect of Ipriflavone In Vivo.

This study aimed to clarify the effects of ipriflavone, which effectively reduces KIAA1199 activity, on osteoarthritis (OA) development and progression in an in vivo OA mouse model. The OA model mice were divided into the ipriflavone (200 mg/kg/day) group and the control group. OA onset and progression were evaluated with the Mankin score, and KIAA1199 expression and hyaluronan (HA) accumulation were analyzed by immunostaining. The molecular weight of HA in the cartilage tissue and serum HA concentration were analyzed by chromatography and competitive HA enzyme-linked immunoassay. The effects of ipriflavone on the bovine cartilage explant culture under the influence of IL-1β were also investigated. In the ipriflavone group, Safranin-O stainability was well-preserved, resulting in significant reduction of the Mankin score (p = 0.027). KIAA1199 staining positivity decreased and HA stainability was preserved in the ipriflavone group. The serum HA concentration decreased, and the molecular weight of HA in the cartilage tissue increased in the ipriflavone group. The results of the cartilage explant culture indicated that ipriflavone could reduce GAG losses and increase the molecular weight of HA. Thus, ipriflavone may have an inhibitory effect on OA development/progression. Ipriflavone could be a therapeutic drug for OA by targeting KIAA1199 activity.

Training-induced impairment of endothelial function in track and field female athletes

Professional athletes are often exposed to high training loads that may lead to overfatigue, overreaching and overtraining that might have a detrimental effects on vascular health. We determined the effects of high training stress on endothelial function assessed by the flow-mediated dilation (FMD) and markers of glycocalyx shedding. Vascular examination as well as broad biochemical, hormonal and cardiometabolic evaluation of sprint and middle-distance female runners were performed after 2 months of preparatory training period and compared to age-matched control group of women. Female athletes presented with significantly reduced FMD (p < 0.01) and higher basal serum concentrations of hyaluronan (HA) and syndecan-1 (SDC-1) (p < 0.05 and p < 0.001, respectively), that was accompanied by significantly lower basal serum testosterone (T) and free testosterone (fT) concentrations (p < 0.05) and higher cortisol (C) concentration (p < 0.05). It resulted in significantly lower T/C and fT/C ratios in athletes when compared to controls (p < 0.01). Moreover, fT/C ratio were significantly positively correlated to FMD and negatively to HA concentrations in all studied women. Accordingly, the training load was significantly negatively correlated with T/C, fT/C and FMD and positively with the concentrations of HA and SDC-1. We concluded that young female track and field athletes subjected to physical training developed impairment of endothelial function that was associated with anabolic-catabolic hormone balance disturbances. Given that training-induced impairment of endothelial function may have a detrimental effects on vascular health, endothelial status should be regularly monitored in the time-course of training process to minimalize vascular health-risk in athletes.

Circulating hyaluronan as a marker of endothelial glycocalyx damage in dogs with myxomatous mitral valve disease and dogs in a hypercoagulable state

The endothelial glycocalyx (eGlx) lines the luminal surface of endothelial cells, maintaining vascular health. Glycocalyx damage is pathophysiologically important in many diseases across species however few studies have investigated its breakdown in naturally occurring disease in dogs. The aims of the study were to investigate eGlx damage in dogs with myxomatous mitral valve disease (MMVD) diagnosed on echocardiography, and dogs in a hypercoagulable state diagnosed using thromboelastography (TEG), by measuring serum hyaluronan concentrations. Serum hyaluronan was quantified in dogs with MMVD (n = 27), hypercoagulability (n = 21), and in healthy controls dogs (n = 18). Serum hyaluronan concentrations were measured using a commercially-available ELISA validated for use in dogs. Hyaluronan concentrations were compared among groups using Kruskal-Wallis tests, and post-hoc with Dunn’s tests. Serum hyaluronan concentrations (median [range]) were significantly increased in dogs with MMVD (62.4 [22.8–201] ng/mL; P = 0.031) and hypercoagulability (92.40 [16.9–247.6] ng/mL; P < 0.001) compared to controls (45.7 [8.7–80.2] ng/mL). Measurement of serum hyaluronan concentration offers a clinically applicable marker of eGlx health and suggests the presence of eGlx damage in dogs with MMVD and dogs in a hypercoagulable state.

Serum levels of soluble FMS-like tyrosine kinase 1 and endothelial glycocalyx components in early- and late-onset preeclampsia

Introduction The most popular model of preeclampsia (PE) is a two-stage one in which the first stage involves a decreased perfusion of the placenta and the second stage is characterized by maternal endothelial injury and dysfunction. This model seems to be more appropriate for early-onset PE, than for the late-onset disease, as in the case of the latter the event of reduced placental perfusion seems is less obvious. The aim of the study was to assess the possible correlations between the serum levels of soluble FMS-like tyrosine kinase 1 (sFlt-1) and the components of endothelial glycocalyx (EG), namely syndecan −1 (SDC-1) and hyaluronan (HA), as the markers of endothelial damage, in patients with early- and late-onset PE. Materials and methods The study was conducted among 60 women in their late second and third trimester of the singleton pregnancy, including 20 patients with early-onset PE, 20 with late-onset PE, and 20 women with normal pregnancy, who served as the control group. All patients were hospitalized between 2015 and 2018 at the Division of Reproduction of Poznan University of Medical Sciences. The women in the control group were matched by gestational age with the patients in the study groups. Results The median serum level of sFlt-1 was the highest in the patients with early-onset PE (3.53 (2.73–4.5) pg/ml) but it was not statistically different from the level in the patients with late-onset PE (3.14 (2.2–3.4) pg/ml). The mean serum level of SDC-1 also did not differ significantly between the two groups of patients with PE (6.17 ± 2.2 ng/ml in early-onset PE; 6.42 ± 2.2 ng/ml in late-onset PE). Both values of SDC-1 were significantly lower than that in the healthy pregnant women (11 ± 2.62 ng/ml, p < .001). The median concentrations of HA did not differ between patients with early- (236.6 (101.1–351.9) ng/ml) and late-onset PE (234.7 (46.8–324.2) ng/ml). However, the levels in these study groups were significantly higher than in the control group (113.9 (30.9–379.8) ng/ml, p < .001). There was no significant correlation found between the serum concentrations of sFlt-1 and both HA and SDC-1; however, such trend was noticed between the serum concentrations of sFlt-1 and HA in patients with early-onset PE, but not in those with the late-onset disease Conclusions Evaluation of serum concentrations of HA in patients with PE was found to be more useful in the assessment of endothelial injury, compared to the assessment of SDC-1.The degree of EG damage was comparable in patients with early- and late-onset PE. The pathomechanism of the damage seems to be more sFlt-1 dependent in patients with early- onset PE than in the case of late-onset disease. The two-stage model of PE is more appropriate for early - onset PE, whereas the pathophysiology of the late-onset disease is rather more complex and heterogenous.

The Diagnostic Usefulness of Circulating Profile of Extracellular Matrix Components: Sulfated Glycosaminoglycans (sGAG), Hyaluronan (HA) and Extracellular Part of Syndecan-1 (sCD138) in Patients with Crohn's Disease and Ulcerative Colitis.

The described research focused on the diagnostic usefulness of sulfated glycosaminoglycans (sGAG), hyaluronan (HA), and extracellular part of syndecan-1 (sCD138) as new markers related to extracellular matrix (ECM) remodeling in the intestine during the two most common forms of inflammatory bowel diseases (IBD), i.e., ulcerative colitis (UC) and Crohn’ disease (CD). Inflammatory markers belonging to ECM components were assessed in serum of patients with IBD using an immunoenzymatic method (HA and sCD138) and a method based on the reaction with dimethylmethylene blue (sulfated GAG). Measurements were carried out twice: at baseline and after one year of therapy with prednisone (patients with CD) or adalimumab (patients with UC). No quantitative changes were observed in serum sGAG, HA, and sCD138 concentrations between patients newly diagnosed with CD and the healthy group. In the case of patients with UC, the parameter which significantly differentiated healthy subjects and patients with IBD before biological therapy was HA. Significant correlation between serum HA level and inflammation activity, expressed as Mayo score, was also observed in patients with UC. Moreover, the obtained results have confirmed that steroid therapy with prednisone significantly influenced the circulating profile of all examined ECM components (sGAG, HA, and sCD138), whereas adalimumab therapy in patients with UC led to a significant change in only circulating sGAG levels. Moreover, the significant differences in serum HA levels between patients with UC and CD indicate that quantification of circulating HA may be useful in the differential diagnosis of CD and UC.

An exploratory study to investigate the association between age, physical activity, femoral trochlear cartilage thickness and biomarkers of tissue metabolism in adult males

PurposeTo investigate the association between age, physical activity, femoral trochlear cartilage thickness and biomarkers of tissue metabolism in a cross-sectional sample of adult males. This study utilizes several emerging biomarkers that have been associated with early joint degenerative changes; serum COMP (cartilage oligomeric matrix protein), HA (hyaluronan) and lubricin.MethodsEighty-one males (age: mean (range): 43(18–70) years; body mass index: 25.2 (21.0–30.6) kg/m2) volunteered. Resting serum COMP, HA and lubricin concentrations were determined via commercially available enzyme-linked immunosorbent assay (ELISA) and femoral trochlear cartilage thickness via supra-patellar ultrasound imaging. Physical activity levels were assessed using questionnaires. Statistical analyses were performed using correlation and regression analyses.ResultsAge was correlated with lateral trochlear cartilage thickness (r = − 0.372; p < 0.01) and serum COMP (r = 0.342; p < 0.01). 7-day physical activity was correlated with serum COMP (r = 0.357, p < 0.01), and 12-month physical activity with both lateral trochlear cartilage thickness (r = 0.340, p = 0.01) and serum HA (r = 0.296, p < 0.05). Regression analyses revealed that age significantly accounted for the variability in lateral cartilage thickness and serum COMP, following the adjustment for potential cofounders. However, the association between age and lateral trochlear cartilage thickness was not moderated by physical activity levels (all p > 0.05).ConclusionThis study indicates that older age may be associated with thinner lateral trochlear cartilage and higher cartilage turnover. Being physically active may also be positive for lateral trochlear cartilage thickness. However, overall, both age and physical activity level only account for a small amount of the variability in cartilage thickness and serum biomarkers.

Markers of Endothelial Injury and Dysfunction in Early- and Late-Onset Preeclampsia.

With regard to differences in the clinical symptoms of preeclampsia (PE), the degree of endothelial dysfunction may differ between early and late-onset preeclampsia (EOP and LOP). The authors of this study examined it by assessing the endothelial injury level in women with EOP (20 patients) and LOP (20 patients) and in normotensive pregnant women (20 patients) in their late second and third trimesters of pregnancy, using the two markers—the serum concentration of hyaluronan (HA) and the serum level of soluble vascular cell adhesion molecule-1 (sVCAM-1). The serum concentrations of HA and sVCAM-1 did not differ significantly between the EOP and LOP patients. However, these were statistically higher than that of the control group participants (p < 0.05; p < 0.001). A significant correlation between the levels of HA and sVCAM-1 was found both in the entire group of patients with preeclampsia (p = 0.0277) and in women with late-onset disease (p = 0.0364), but not in the patients with early-onset preeclampsia (p = 0.331). The obtained results indicated a comparable level of endothelial injury in the two types of PE. The presence of a similar degree of endothelial injury in patients with EOP and LOP should create awareness among all clinicians about the possible fatal complications in both groups of patients with PE.

Proteoglycan-4 and hyaluronan composition in synovial fluid and serum from clinical equine subjects: relationship to cartilage boundary lubrication and viscosity of synovial fluid

ABSTRACT Purpose: In experimental models of equine joint-injury and osteoarthritis synovial fluid (SF) composition (proteoglycan-4, hyaluronan) can vary, along with changes to SF mechanical function (lubrication, viscosity). The study hypotheses were a) clinical equine joint-injury and disease results in altered SF composition and diminished mechanical function, and b) serum composition (proteoglycan-4 or hyaluronan) changes concurrently. The objectives were to characterize composition (proteoglycan-4, hyaluronan), and function of SF and serum from normal horses compared to clinical groups: osteoarthritis, acute-joint-injury, and osteochondrosis. Materials and Methods: Equine samples of SF (from various joints) and blood were collected at the point-of-care. Proteoglycan-4 concentrations were measured by amplified-luminescence-proximity-assay and enzyme-linked-immunosorbent-assay in SF and serum, respectively. Molecular-weight of hyaluronan was characterized by agarose-gel-electrophoresis, and concentrations were measured by enzyme-linked-immunosorbent-assay kit. Biomechanical function of SF was characterized by an in vitro cartilage-on-cartilage friction test, and viscosity test. Results: SF proteoglycan-4 concentration increased in acute-joint-injury (1185 ± 276 versus normal 205 ± 106 µg/mL, µ± SEM, p < 0.01), with increased percentage of lower molecular-weight hyaluronan in acute-joint-injury and osteochondrosis. SF and serum proteoglycan-4 concentrations were correlated in normal horses (r2 = 0.85, p < 0.05), but not in clinical groups. Cartilage-lubricating ability was unchanged, although steady-shear viscosity of acute-joint-injury SF decreased from normal. Conclusion: Composition of SF from cases of equine acute-joint-injury changed; both proteoglycan-4 concentration and hyaluronan molecular-weight were altered, with decreased SF viscosity, but no associated changes to serum. Serum proteoglycan-4 and hyaluronan concentrations alone may not be useful biomarkers for equine joint-injury or disease.

On-the-Scene Hyaluronan and Syndecan-1 Serum Concentrations and Outcome after Cardiac Arrest and Resuscitation.

Background It is not predictable which patients will develop a severe inflammatory response after successful cardiopulmonary resuscitation (CPR), also known as “postcardiac arrest syndrome.” This pathology affects only a subgroup of cardiac arrest victims. Whole body ischemia/reperfusion and prolonged shock states after return of spontaneous circulation (ROSC) may both contribute to this devastating condition. The vascular endothelium with its glycocalyx is especially susceptible to initial ischemic damage and may play a detrimental role in the initiation of postischemic inflammatory reactions. It is not known to date if an immediate early damage to the endothelial glycocalyx, detected by on-the-scene blood sampling and measurement of soluble components (hyaluronan and syndecan-1), precedes and predicts multiple organ failure (MOF) and survival after ROSC. Methods 15 patients after prehospital resuscitation were included in the study. Serum samples were collected on the scene immediately after ROSC and after 6 h, 12 h, 24 h, and 48 h. Hyaluronan and syndecan-1 were measured by ELISA. We associated the development of multiple organ failure and 30-day survival rates with these serum markers of early glycocalyx damage. Results Immediate serum hyaluronan concentrations show significant differences depending on 30-day survival. Further, the hyaluronan level is significantly higher in patients developing MOF during the initial and intermediate resuscitation period. Also, the syndecan-1 levels are significantly different according to MOF occurrence. Conclusion Serum markers of glycocalyx shedding taken immediately on the scene after ROSC can predict the occurrence of multiple organ failure and adverse clinical outcome in patients after cardiac arrest.

Respective roles of hyaluronidases 1 and 2 in endogenous hyaluronan turnover.

We studied the physiologic roles of the hyaluronidase (HYAL) 1 and HYAL2 in hyaluronan (HA) turnover. HA was localized and quantified using HA binding proteins in various tissues of Hyal1(-/-) and Hyal2(-/-) mice (knockout mice) as well as control mice. HA MW was determined using gel filtration chromatography. HA endocytosis in liver nonparenchymal cells (NPCs) was quantified in vivo Both Hyal1 and Hyal2 knockout mice showed HA accumulation in peripheral tissues without changes in HA MW distribution. HYAL2 deficiency induced buildup of very high MW (>3.10(6) Da) HA in lymph and serum with severe lymph node distortion. The lack of HYAL2 also impaired high MW HA endocytosis by liver NPCs. HYAL1 deficiency led to a moderate increase in serum HA concentration without changes in HA MW distribution and to HA overload of liver NPCs. Wild-type C57BL/6 mice served as controls. In HA injection experiments, saline-injected mice served as additional controls. We conclude that: 1) HYAL1 and HYAL2 are both needed for tissue HA catabolism; 2) HYAL2 is required for high MW HA clearance in lymph nodes and plasma and for HA endocytosis by liver NPCs; and 3) the main role of HYAL1 is HA degradation within liver NPCs.-Bourguignon, V., Flamion, B. Respective roles of hyaluronidases 1 and 2 in endogenous hyaluronan turnover.

Suppression of Hyaluronan Synthesis Alleviates Inflammatory Responses in Murine Arthritis and in Human Rheumatoid Synovial Fibroblasts

To clarify the roles of hyaluronan (HA) in joint inflammation and the process of joint destruction, using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, in a mouse model of collagen-induced arthritis (CIA) and in a monolayer culture of fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis. DAB/1J mice were immunized with type II collagen. The effects of 4-MU were evaluated by the physiologic arthritis score, paw swelling, the histologic arthritis score, and expression of matrix metalloproteinase 3 (MMP-3) and MMP-13 in chondrocytes and synovial tissue. In vitro, the effect of 4-MU on messenger RNA and protein expression of MMP-1 and MMP-3 was determined. The effects of 4-MU on HA deposition and on serum/medium concentrations of HA were analyzed using biotinylated HA binding protein staining and an HA binding assay, respectively. Treatment with 4-MU in mice with CIA dramatically decreased the severity of arthritis (based on the arthritis score), paw thickness, and histopathologic changes. MMP-3 and MMP-13 expression in chondrocytes and synovial cells was significantly inhibited by 4-MU in vivo. Treatment with 4-MU also inhibited MMP-1 and MMP-3 expression in tumor necrosis factor α-stimulated FLS, in a dose-dependent manner. The 4-MU-induced decreases in the serum HA concentration in mice with CIA and in "medium" and "pericellular" HA concentrations in cultured FLS support the contention that the inhibitory mechanism of 4-MU is mediated by HA suppression. Reduced disease activity induced by 4-MU in mice with CIA revealed HA to be a crucial regulator in the course of arthritis. Therefore, 4-MU is a potential therapeutic agent in arthritis, and its inhibitory mechanism is possibly mediated by suppression of HA synthesis.

Clinicopathological Role of Serum-Derived Hyaluronan-Associated Protein (SHAP)-Hyaluronan Complex in Endometrial Cancer.

The role of hyaluronan (HA), serum-derived HA-associated protein (SHAP)-HA complex and hyaluronan synthase (HAS) in endometrial carcinomas was investigated. The relationship of metalloproteinase (MMP) and its inhibitor (TIMP) with HA and the SHAP-HA complex was also examined. The expression of HAS1 was related to the depth of myometrial invasion and lymph-vascular space involvement. The serum levels of HA, SHAP-HA complex, MMP-9, and TIMP-1 were increased in related with the depth of myometrial invasion, histological grade and lymph-vascular space involvement. They were also higher in the HAS1-positive group compared to -negative group. The serum concentrations of HA and SHAP-HA complex had a significant correlation with the MMP-9 and TIMP-1. The patients with elevated SHAP-HA complex had the shorter disease-free survival. The multivariate analysis revealed that the SHAP-HA complex was the independent variable for disease-free survival of endometrial cancer patients. In conclusion, the elevation of serum SHAP-HA complex depended on the HAS1 expression and the SHAP-HA complex is a useful marker to predict disease recurrence in endometrial cancer patients. The SHAP-HA complex may promote the lymph-vascular space involvement and the synthesis and activation of MMP-9 and TIMP-1 in the progression of endometrial cancer.

Serum hyaluronan levels in oral cancer patients

Hyaluronan (HA) is most likely associated with tumor invasion and metastasis. Studies have shown that HA levels are often increased in serum of patients with various malignant tumors. The purpose of this study was to determine the levels of serum hyaluronan in patients with oral cancer and evaluate the value of serum HA in adjuvant diagnosis, staging and monitoring treatment response in these patients. Eighty-four hospitalized patients with oral cancer, 65 patients with benign tumors in the oral and maxillofacial region and 67 healthy individuals were included in this investigation. Venous blood was collected from these patients and the healthy individuals before therapy. One week after therapy, venous blood was collected once again in 43 patients with oral cancer. Serum samples were obtained and serum HA levels examined. The serum HA concentration was significantly higher in oral cancer patients than in patients with benign tumors and in healthy controls (P<0.05). The serum HA level in patients with stages III and IV disease was higher than in patients with stages I and II disease, but there was no significant difference in the HA level between stages I and II nor between stages III and IV (P>0.05). After a complete treatment the HA levels in patients with oral cancer became lower than before treatment, but the difference was not significant (P>0.05). The results of this study suggest that the determination of HA levels may provide additional information in diagnosis of oral cancer, but its usefulness as an adjunct in clinical staging and in monitoring treatment response was limited.

Hyaluronan (HA) and Serum-Derived Hyaluronan-Associated Protein (SHAP)-HA Complex as Predictive Markers of Cervical Ripening in Premature Labor

The purpose of this study is to investigate whether serum hyaluronan (HA) and serum-derived HA-associated proteins (SHAP)-HA complex predict cervical ripening and premature delivery. Sera were obtained from 64 women with normal pregnancies, 20 with full term delivery, and 13 with threatened premature labor. Concentrations of HA and SHAP-HA complex in serum were measured by sandwich ELISA. Serum concentrations of HA and SHAP-HA complex did not differ within first, second, and third trimester groups. The serum SHAP-HA complex was elevated in the full term labor group more than in the third trimester group; however, the concentrations of serum HA did not differ between both groups. The HA and SHAP-HA complex levels in sera were higher in the premature labor group than in the second trimester group. In the premature labor group, the SHAP-HA complex levels were higher in the cases with Bishop scores more than 4 points when compared with the cases with Bishop scores of 4 points or less. Increased levels of SHAP-HA complex in sera are possible predictive markers for cervical ripening in premature labor.

Does the Surface Structure of Implants Have an Impact on the Formation of a Capsular Contracture?

The formation of a fibrous capsule around a silicone breast implant is part of a physiologic foreign body reaction after breast augmentation. In contrast, the formation of a capsular contracture is a local complication of unknown cause. This study aimed to discover whether the surface structure of the implant (textured vs smooth) has any impact on the formation of a capsular contracture. This prospective study included 48 female patients with unilateral capsular fibrosis grades 1 to 4 in Baker's clinical scaling system. Of these patients, 14 received implants with a textured surface (Mentor), and 34 received implants with a smooth surface (Mentor). The implants all were placed in a submuscular position by the same experienced plastic surgeon. The clinical data were assessed using standardized patient questionnaires. For histologic diagnosis, operatively excised capsular tissue was examined. Preoperatively, venous blood samples for determining serum hyaluronan concentrations were taken from the patients. The control group consisted of 20 patients without capsular fibrosis. The separate analysis of clinical data for the patients with textured and those with smooth-surfaced breast implants showed a slightly reduced degree of symptoms for the patients with textured silicone breast implants, as compared with those who had smooth-surfaced implants. The histologic assessment of the fibrosis showed a symmetric distribution for Wilflingseder scores 1 to 3 (29% each), whereas 13% of the capsular tissues could be assigned to Wilflingseder score 4. In contrast, the histologic assessment of the patients with smooth-surfaced implants predominantly showed a Wilflingseder score of 3 (65%). The serologic investigations via enzyme-linked immunoassay (ELISA) showed serum hyaluronan concentrations of 10 to 57 ng/ml (25.0 +/- 11.7 ng/ml). Therefore, no statistically significant differences in terms of serum hyaluronan levels could be determined between the two groups of patients. In comparison with the control group, the patients with implants showed elevated serum hyaluronan levels (p < 0.05). The histologic examination and serum hyaluronan concentration analysis showed no statistically significant difference between smooth-surfaced and textured implants (Mentor) with respect to the development of capsular contracture. On the other hand, the severity of capsular contracture showed a positive linear correlation with the degree of local inflammatory reactions, which were independent of the implant surface.

Raised Serum Chondroitin Sulfate Epitope Level in Ovarian Epithelial Cancer

To determine the value of serum chondroitin sulfate epitope WF6 and hyaluronan (HA) levels as a biomarker for early detection of ovarian epithelial cancer and other gynecological disorders. Serum WF6 CS epitope and HA were measured in 91 patients with ovarian epithelial cancer, 39 patients with non-cancer gynecological disorders and 30 healthy women. Serum chondroitin sulfate (CS) WF6 epitope was determined by a competitive immunoassay with the monoclonal antibodies WF6, which specifically recognizes an epitope in native CS chains. In addition, serum HA concentration was measured by an ELISA-based assay with a biotinylated affinity HA-binding proteins. The serum concentration of CS (WF6) epitope was highly increased in epithelial types of ovarian cancer and at all stages of development (p < 0.005). Serum HA in ovarian cancer patients was significantly higher than normal controls (p < 0.05). These results reflect changes in ECM metabolism in progressive ovarian cancer, which cause an increase in serum CS epitopes and HA. Therefore, serum CS epitopes may provide useful biomarkers for cancers and other disorders of the ovary. Measurement of serum HA provided complementary information, which may be useful as a discriminator between benign ovarian disorders and malignant ovarian diseases.

Serum Hyaluronan Concentration as a Marker of Angiopathy in Patients with Diabetes Mellitus

Accumulation of hyaluronan (HA) around smooth muscle cells in lesions of atherosclerosis in diabetic patients suggests that this protein plays an important role in diabetic angiopathy. The aim of this study was to determine the correlation between serum HA concentrations and diabetic angiopathy. Diabetic patients treated with or without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n = 95). We also included 20 non-diabetic control subjects. We measured serum levels of HA, body mass index (BMI), fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, glycated albumin (GA), high sensitivity CRP (hs-CRP), monocyte chemoattractant protein (MCP)-1 and evaluated diabetes mellitus history, drug use and presence of related complications. Serum HA levels were significantly (P<0.05) higher in diabetic patients (83.6 +/- 5.6 ng/ml, mean +/- SEM) than in normal subjects (41.7 +/- 12 ng/ml). In diabetic patients, serum HA concentration significantly correlated with FPG, HbA1c, GA, triglyceride and also significantly correlated with BMI, hs-CRP and MCP-1 and tended to be higher in diabetic patients with complications than in those without such complications. Our data suggest that serum HA level correlates with poor blood glucose control and diabetic angiopathy and that it could be used as a marker of diabetic angiopathy.

Serologic and Histologic Findings in Patients with Capsular Contracture After Breast Augmentation with Smooth Silicone Gel Implants: Is Serum Hyaluronan a Potential Predictor?

In this study, breast implant capsular tissues and blood samples from 25 cases were studied to characterize the relationship between capsular findings and serum analysis. The serum fibrosis indexes hyaluronan and the aminoterminal propeptide of procollagen type III (PIIINP) are fairly well correlated in several other studies with the inflammation grade and fibrosis in patients with progressive fibrotic disorders such as liver cirrhosis. The study enrolled 25 female patients (average age, 40 +/- 12 years) with capsular contracture after bilateral cosmetic breast augmentation using smooth silicone gel implants (Mentor). The implants were placed in a submuscular position through an incision in the inframammary fold. The implant removals were prompted by development of capsular fibrosis (Baker grades 1-4). Samples of capsular tissue were obtained from all the patients for standard histologic and immunohistochemical analyses. Blood samples were drawn from all the patients immediately before surgery. Sera from 20 healthy female patients (average age, 34 +/- 9 years) who had undergone plastic surgery for reduction mammaplasty were used as controls. Histology. Capsular tissue was significantly thicker in patients with grades 3 and 4 contracture than in women with grade 2 contracture according the classification by Baker. There was a moderate (n = 15) or severe (n = 10) chronic inflammatory reaction in the capsules around the implants. Fibroblasts and macrophages represented the major cell population found in the fibrous capsules. In addition, activated CD4+ cells were detected. An inner layer with synovia-like metaplasia and multinucleated giant cells was found. Fibroblast-like cells formed the most common cell type in the capsules, along with macrophages, scattered polymorphonuclear leukocytes, lymphocytes, plasma cells, and mast cells. Serum analysis. There was a significantly higher level (p < 0.05) of hyaluronan serum concentration in patients with capsular contracture (26 +/- 14 microg/l) than in control subjects (12 +/- 6 microg/l). There was a positive correlation between the grade of capsular contracture (Baker 1-4) and the hyaluronan serum concentration (Baker 1-2: 15 +/- 3 microg/l; Baker 3-4: 35 +/- 12 microg/l) (r2 = 0.73; p < 0.05). : In this study, serum hyaluronan levels were significantly elevated in patients with constrictive fibrosis after breast augmentation, and there was a positive correlation with the stage of capsular contracture. Serum hyaluronan concentration may help in defining patients at risk for capsular fibrosis. If treatment with new drugs can be started as a preventive measure, it may be possible to reduce the rate of patients who require surgical intervention.

Serum hyaluronidase aberrations in metabolic and morphogenetic disorders

Hyaluronidases are endo-glycosidases that degrade both hyaluronan (hyaluronic acid) (HA) and chondroitin sulfates. Deficiency of hyaluronidase activity has been predicted to result in a phenotype similar to that observed in mucopolysaccharidosis (MPS). In the present study, we surveyed a variety of patients with phenotypes similar to those observed in MPS, but without significant mucopolysacchariduria to determine if some are based on aberrations in serum hyaluronidase (Hyal-1) activity. The study included patients with well-characterized dysmorphic disorders occurring on genetic basis, as well as those of unkown etiology. The purpose of the study was to establish how wide spread were abnormalities in levels of circulating Hyal-1 activity. A simple and sensitive semi-quantitative zymographic procedure was used for the determination of activity. Levels of both beta-N-acetylglucosaminidase and beta-glucuronidase whose activities contribute to the total breakdown of hyaluronan (HA) were also measured, as well as the concentration of circulating HA. Among 48 patients with bone or connective tissue abnormalities, low levels of Hyal-1 activity were found in six patients compared to levels in 100 healthy donors (2.0-3.2 units/microL vs 6(+/- 1 SE) units/microL). These six patients exhibited a wide spectrum of clinical abnormalities, in particular shortened extremities: they included three patients with unknown causes of clinical symptoms, one patient with Sanfilippo disease, one of the seven patients with achondroplasia, and one with hypophosphotemic rickets. Normal levels of serum Hyal-1 activities were found in patients with Morquio disease, GM1 gangliosidosis, I cell-disease, 6 of the 7 patients with achondroplasia, Marfan's-syndrome and Ehlers-Danlos syndrome. No patient totally lacked serum Hyal-1 activity. Serum HA concentration was elevated in patients with Sanfilippo A and I-cell disease. Determination of serum and leukocyte Hyal-1 and serum HA may be useful to evaluate patients with metabolic and morphogenetic disorders.

Effect of nimesulide on the serum levels of hyaluronan and stromelysin-1 in patients with osteoarthritis: a pilot study

This prospective preliminary single-blind study was conducted in patients suffering from osteoarthritis (OA) and requiring non-steroidal anti-inflammatory drugs (NSAIDs) to determine to what extent nimesulide (200 mg/day) and ibuprofen (1200 mg/day) could induce significant changes in the serum levels of matrix metalloproteinase-3 (MMP-3), tissue inhibitor-1 of MMPs (TIMP-1), hyaluronan (HA) and YKL-40 after a therapeutic time period of 28 days. The four biochemical parameters were assessed by using immunoassays. Nimesulide significantly reduced the serum levels of both HA and MMP-3, whereas ibuprofen increased moderately but significantly the serum concentrations of MMP-3 and had no effect on the serum concentrations of HA. The two NSAIDs were unable to change the serum levels of both TIMP-1 and YKL-40. These results suggest that nimesulide might have a favourable effect on the metabolism of OA joints.