Markers Of Cartilage Degradation Research Articles

Monosodium iodoacetate induces Cartilage degradation and inflammation in rats in a dose- and time-dependent manner

Monosodium iodoacetate (MIA) is a widely recognized agent for inducing cartilage degradation and inflammation in animal models. In this study, we systematically investigated the dose- and time-dependent effects of MIA on cartilage degradation in the knees of rats. We evaluated knee diameter, knee bend score, and the levels of pro-inflammatory cytokines (IL-1 and IL-8) and cartilage degradation markers (CTX-II) to gain insights into cartilage damage and inflammation progression. Wistar rats were categorized into groups receiving various doses of MIA via intra-articular injection (0.1 mg, 0.5 mg, 1 mg, 3 mg, and 5 mg) and were observed at multiple time intervals (2, 4, 6, 8, 10, and 12 weeks). We measured knee diameter to gauge joint swelling, assigned knee bend scores to assess functional limitations, and analyzed synovial fluid samples for IL-1β, IL-8, and CTX-II levels. Our data show that low-dose MIA increases pain sensitivity, knee diameter, inflammatory cytokines IL-1β and IL-8, and CTX-II levels, which progress slowly over 12 weeks. On the other hand, higher dosages of MIA caused cartilage deterioration after two weeks, followed by an increase in inflammatory cytokines. This research sheds light on MIA administration's dose- and time-dependent effects on cartilage breakdown and inflammation in rat knee joints. Analyzing knee diameter, knee bend score, IL-1β, IL-8, and CTX-II as evaluation parameters provides a multidimensional perspective of cartilage injury and inflammatory dynamics. These findings help us comprehend cartilage-related illnesses and have implications for future research on therapeutic approaches for cartilage disorders.

Deficiency of Cbfβ in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways.

Osteoarthritis (OA) is the most prevalent degenerative joint disorder, causing physical impairments among the elderly. Core binding factor subunit β (Cbfβ) has a critical role in bone homeostasis and cartilage development. However, the function and mechanism of Cbfβ in articular cartilage and OA remains unclear. We found that Cbfβf/fAggrecan-CreERT mice with Cbfβ-deficiency in articular cartilage developed a spontaneous osteoarthritis-like phenotype with articular cartilage degradation. Immunofluorescence staining showed that Cbfβf/fAggrecan-CreERT mice exhibited a significant increase in the expression of articular cartilage degradation markers and inflammatory markers in the knee joints. RNA-sequencing analysis demonstrated that Cbfβ orchestrated Hippo/Yap, TGFβ/Smad, and Wnt/β-catenin signaling pathways in articular cartilage, and Cbfβ deficiency resulted in the abnormal expression of downstream genes involved in maintaining articular cartilage homeostasis. Immunofluorescence staining results showed Cbfβ deficiency significantly increased active β-catenin and TCF4 expression while reducing Yap, TGFβ1, and p-Smad 2/3 expression. Western blot and qPCR validated gene expression changes in hip articular cartilage of Cbfβ-deficient mice. Our results demonstrate that deficiency of Cbfβ in articular cartilage leads to an OA-like phenotype via affecting Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways, disrupting articular cartilage homeostasis and leading to the pathological process of OA in mice. Our results indicate that targeting Cbfβ may be a potential therapeutic target for the design of novel and effective treatments for OA.

Astaxanthin as a Potent Antioxidant for Promoting Bone Health: An Up-to-Date Review.

In recent years, bone loss and its associated diseases have become a significant public health concern due to increased disability, morbidity, and mortality. Oxidative stress and bone loss are correlated, where oxidative stress suppresses osteoblast activity, resulting in compromised homeostasis between bone formation and resorption. This event causes upregulation of bone remodeling turnover rate with an increased risk of fractures and bone loss. Therefore, supplementation of antioxidants can be proposed to reduce oxidative stress, facilitate the bone remodeling process, suppress the initiation of bone diseases, and improve bone health. Astaxanthin (3,3'-dihydroxy-4-4'-diketo-β-β carotene), a potent antioxidant belonging to the xanthophylls family, is a potential ROS scavenger and could be a promising therapeutic nutraceutical possessing various pharmacological properties. In bone, astaxanthin enhances osteoblast differentiation, osteocytes numbers, and/or differentiation, inhibits osteoclast differentiation, cartilage degradation markers, and increases bone mineral density, expression of osteogenic markers, while reducing bone loss. In this review, we presented the up-to-date findings of the potential anabolic effects of astaxanthin on bone health in vitro, animal, and human studies by providing comprehensive evidence for its future clinical application, especially in treating bone diseases.

Efficacy of a proprietary combination of Tamarindus indica seeds and Curcuma longa rhizome extracts in osteoarthritis: a clinical investigation.

NXT15906F6 (TamaFlex™) is a proprietary blend containing standardized Tamarindus indica seeds and Curcuma longa rhizome extracts. Earlier, NXT15906F6 supplementation demonstrated reduced knee joint pain and improved musculoskeletal functions in healthy and knee osteoarthritis (KOA) subjects. The present randomized, double-blind, placebo-controlled study was focused on validating the clinical efficacy of NXT15906F6 in a larger number of subjects with KOA. Male and female subjects (age: 40-70 years; body mass index [BMI]: 20-29 kg/m2] were randomized into three groups receiving placebo (n = 50), NXT15906F6 (n = 50) or a blend of C. longa and Boswellia serrata extracts (CLBS) (n = 50). Subjects consumed 250 mg NXT15906F6, 1,000 mg CLBS or a matched placebo daily after breakfast over a period of 30 consecutive days. The primary efficacy outcome was the improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and the secondary efficacy measures included various tests on joint pain and musculoskeletal functions and evaluations ofserum high-sensitivity C-reactive protein (hs-CRP) and a cartilage degradation marker, C-terminal telopeptide of type II collagen in urine (uCTX-II). NXT15906F6 significantly (P < 0.001) reduced the WOMAC scores and improved musculoskeletal function scores in the participants as compared with baseline and placebo. NXT15906F6 participants reduced knee pain and improved musculoskeletal functions as early as day 5 of supplementation. In contrast, CLBS supplementation failed to show early efficacies in pain and functional scores, except for 30s-CST and primary knee flexion. The NXT1506F6-supplemented participants significantly reduced serum hs-CRP and uCTX-II levels from baseline and as compared with the placebo. Both supplementations did not alter the subjects' clinical chemistry, hematology, and vital parameters. The anti-inflammatory botanical composition NXT15906F6 supplementation mitigated joint pain and improved musculoskeletal functions and joint motility in KOA subjects. This botanical composition was also well-tolerated by the volunteers.

Bevacizumab suppressed degenerative changes in articular cartilage explants from patients with osteoarthritis of the knee

BackgroundThis study was designed to test the hypothesis that blockade of vascular endothelial growth factor (VEGF) suppresses degenerative changes in articular cartilage from patients with osteoarthritis (OA).MethodsArticular cartilage from eight OA patients was subjected to explant culture for 2 days in the presence or absence of 10 ng/ml recombinant interleukin (IL)-1β. The blocking effect of VEGF was examined by the addition of 10 or 100 ng/ml of bevacizumab. The culture media were harvested, and markers for cartilage degradation were measured by sandwich enzyme-linked immunoassay. Total RNA was isolated from cartilage tissues, and gene expressions associated with the anabolic response were examined by the quantitative real-time polymerase chain reaction.ResultsBevacizumab significantly reduced concentrations of matrix metalloproteinase (MMP)-2, MMP-3, and cartilage oligomeric matrix protein in the culture media with and without IL-1β. Significant suppressive effects of bevacizumab on MMP-9 and MMP-13 were shown only in the presence of IL-1β. Gene expression of Col2a1 was significantly increased by the addition of bevacizumab in the absence of IL-1β.ConclusionBevacizumab inhibits catabolic reactions and stimulates anabolic function in articular cartilage derived from OA patients directly, suggesting a protective effect on articular cartilage from OA progression.

Mass spectrometry imaging spatially identifies complex-type N-glycans as putative cartilage degradation markers in human knee osteoarthritis tissue

N-Glycan alterations contribute to the pathophysiology and progression of various diseases. However, the involvement of N-glycans in knee osteoarthritis (KOA) progression at the tissue level, especially within articular cartilage, is still poorly understood. Thus, the aim of this study was to spatially map and identify KOA-specific N-glycans from formalin-fixed paraffin-embedded (FFPE) osteochondral tissue of the tibial plateau relative to cadaveric control (CTL) tissues. Human FFPE osteochondral tissues from end-stage KOA patients (n=3) and CTL individuals (n=3), aged >55 years old, were analyzed by matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) and liquid chromatography–tandem mass spectrometry (LC-MS/MS). Overall, it was revealed that 22 N-glycans were found in the cartilage region of KOA and CTL tissue. Of those, 15 N-glycans were more prominent in KOA cartilage than CTL cartilage. We then compared sub-regions of KOA and CTL tissues based on the Osteoarthritis Research Society International (OARSI) histopathological grade (1 to 6), where 1 is an intact cartilage surface and 6 is cartilage surface deformation. Interestingly, three specific complex-type N-glycans, (Hex)4(HexNAc)3, (Hex)4(HexNAc)4, and (Hex)5(HexNAc)4, were found to be localized to the superficial fibrillated zone of degraded cartilage (KOA OARSI 2.5-4), compared to adjacent cartilage with less degradation (KOA OARSI 1-2) or relatively healthy cartilage (CTL OARSI 1-2). Our results demonstrate that N-glycans specific to degraded cartilage in KOA patients have been identified at the tissue level for the first time. The presence of these N-glycans could further be evaluated as potential diagnostic and prognostic biomarkers.

The use of collagen type-II as an indicator for assessment regeneration effect post intra-articular pure-PRP injection in KOA patient

Background: knee osteoarthritis (KOA) is a complex disease that causes metabolic, structural, biochemical, and functional alterations in afflicted tissues. Physical examination and radiological findings are the present methods for the diagnosis of knee osteoarthritis. Traditionally, KOA medication focused on symptom management. Clinical trials focused on delaying or reversing disease development have gained popularity in recent years. PRP is among the medicinal approaches used to manage KOA.Purpose: By assessing the cartilage degradation marker collagen-II, the study's aim was to figure out whether the use of pure-PRP may help KOA patients' damaged cartilage layers regenerate. Methods: This non-randomized controlled trial study involved 66 patients with knee OA and 28 healthy control subjects from December 2021 to February 2022. There were 2 categories of knee OA patients: 34 with moderate (grade-3) and 32 with mild (grade-2) KOA. So, every group of KOA patients is divided into three subgroups based to the frequency of injections (single, double, or triple) in addition to severity. Based on clinical and radiological data using the Kellgren-Lawence (KL) 0–4 grading system, the patients' diagnoses and classifications are made. This study was designed at AL-Imam Ali hospital, Babylon governorate, Iraq and approved by the medical human research ethics committee at Al-Qadisiyah university/ collage of medicine. Results: The findings of this investigation show that the serum collagen type-II content was considerably greater in KOA patients were compared to control subjects, and in moderate compared to mild KOA as the severity of the disease progressed. But following pure-PRP injection, the serum level of collagen type-II did not significantly decrease, and increasing the number of injections had no better effect. Conclusions: PRP therapy was generally acceptable for patients in terms of improving symptoms and there were no complications following injection. However, there is insufficient indication that platelet rich plasma regenerates cartilage damage in knee OA patients, as there was no significant decrease in the amount of collagen type-II.

EFFECTS OF WEIGHT CHANGE ON KNEE AND HIP RADIOGRAPHIC MEASUREMENTS AND PAIN OVER 4 YEARS: DATA FROM THE OSTEOARTHRITIS INITIATIVE

Purpose: Osteoarthritis (OA) is present in 10.5% of the US population, often affects large weight-bearing joints such as the hip and knee, and its prevalence increases with higher levels of BMI. Since obesity is a modifiable risk factor for OA, understanding the effects of weight gain and weight loss on hip and knee OA is critical for the development of effective, long-term therapeutic strategies for OA. While studies have shown beneficial effects of weight loss on knee OA including reduced symptomatic outcomes, slower progression of MRI structural outcomes, less inflammation, less knee joint mechanical loads, and reduced serum markers for cartilage degradation, fewer studies have investigated the effects of weight gain on knee OA.

Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K–AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

Sensitive asprosin detection in clinical samples reveals serum/saliva correlation and indicates cartilage as source for serum asprosin

The C-terminal pro-fibrillin-1 propeptide asprosin is described as white adipose tissue derived hormone that stimulates rapid hepatic glucose release and activates hunger-promoting hypothalamic neurons. Numerous studies proposed correlations of asprosin levels with clinical parameters. However, the enormous variability of reported serum and plasma asprosin levels illustrates the need for sensitive and reliable detection methods in clinical samples. Here we report on newly developed biochemical methods for asprosin concentration and detection in several body fluids including serum, plasma, saliva, breast milk, and urine. Since we found that glycosylation impacts human asprosin detection we analyzed its glycosylation profile. Employing a new sandwich ELISA revealed that serum and saliva asprosin correlate strongly, depend on biological sex, and feeding status. To investigate the contribution of connective tissue-derived asprosin to serum levels we screened two cohorts with described cartilage turnover. Serum asprosin correlated with COMP, a marker for cartilage degradation upon running exercise and after total hip replacement surgery. This together with our finding that asprosin is produced by primary human chondrocytes and expressed in human cartilage suggests a contribution of cartilage to serum asprosin. Furthermore, we determined asprosin levels in breast milk, and urine, for the first time, and propose saliva asprosin as an accessible clinical marker for future studies.

Intra-articular Injection of Baicalein Inhibits Cartilage Catabolism and NLRP3 Inflammasome Signaling in a Posttraumatic OA Model

Baicalein has been shown to have chondroprotective potential in vitro. However, its effect on disease modification in osteoarthritis (OA) is largely unknown. The present study is aimed at determining whether baicalein could slow the progression of OA and inhibit OA-related inflammation in a rat model of destabilization of the medial meniscus (DMM) and the underlying mechanisms. The rats subjected to DMM surgery were treated with baicalein (0.8, 1.6, and 3.2 μg/L, 50 μL, once a week) by intra-articular injection for 6 weeks. Dexamethasone (0.4 mg/mL, 50 μL, once a week) was used as a positive control. Histologic grading of cartilage degeneration was performed using the Osteoarthritis Research Society International (OARSI) recommended grading system (on a scale of 0-6). The expression levels of molecules associated with cartilage homeostasis and inflammatory cytokines were analyzed; moreover, the NLRP3 inflammasome activation and cartilage oxidative stress-associated molecules were determined. Baicalein treatment reduced the OARSI score and slowed OA disease progression in a dose-dependent manner within a certain range. Compared with DMM rats, intra-articular injection of baicalein led to (1) reduced levels of inflammatory mediates such as IL-1β and TNF-α, (2) reduced immunochemical staining of MMP-13 and ADAMTS-5, (3) suppressed immunochemical staining loss of type II collagen, (4) reduced expression of cartilage degradation markers including CTX-II and COMP in urine, and (5) inhibited NLRP3 inflammasome activation rather than regulated expression of SOD, GSH, and MDA. In contrast to the administration of baicalein, dexamethasone injection showed similar effects to slow OA progression, while dexamethasone inhibited NLRP3 inflammasome partly through decreasing levels of SOD, GSH, and MDA. This study indicated that baicalein may have the potential for OA prevention and exerts anti-inflammatory effects partly via suppressing NLRP3 inflammasome activation without affecting oxidative stress-associated molecules, and inhibition of cartilage catabolism enzymes in an OA rat model.

Changes of synovial fluid biomarker levels after opening wedge high tibial osteotomy in patients with knee osteoarthritis

The purpose of this study was to evaluate the effects of high tibial osteotomy (HTO) on the biological status of knee osteoarthritis (OA) using joint markers in synovial fluid (SF). Fifty patients with medial compartmental OA of the knee who underwent opening wedge HTO were enrolled. Paired SF samples from the affected knee and arthroscopic evaluation of articular cartilage were collected at the time of HTO surgery and the time of plate removal (postoperative 17±4 months). The concentrations of the following SF biomarkers were measured: interleukin (IL)-1β, IL-6, IL-8, IL-10, tumour necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, MMP-13, vascular endothelial growth factor (VEGF), and cartilage oligomeric matrix protein (COMP). The Knee Society Score (KSS) and hip-knee-ankle (HKA) angle were assessed before and 2 years after HTO. The KSS knee and function scores were significantly improved after HTO (mean changes of 36.4 and 23.7, respectively). The mean HKA angle was altered from mechanical varus (-8.6°) to valgus (5.2°). Concentrations of IL-6, IL-8, MMP-2, MMP-3, MMP-13, VEGF, and COMP in SF were significantly decreased after HTO (mean changes of-49.1%,-30.2%,-31.1%,-26.3%,-30.8%,-42.5%, and-13.7% from preoperative baseline, respectively). The cartilage status was improved in 19 cases (38%) after HTO. However, changes of all biomarkers were not significantly different between subjects with and without an improved cartilage status. SF levels of biochemical markers for cartilage degradation and synovial inflammation were altered after HTO, suggesting an improvement in the OA disease state.

Protective effect of glycyrrhizin on osteoarthritis cartilage degeneration and inflammation response in a rat model

This study was conducted to investigate the protective effects of glycyrrhizin on a rat model of osteoarthritis and elucidate the underlying mechanism. Rat osteoarthritis was established by using medial meniscectomy (MMx) and an anterior cruciate ligament transaction (ACLT). Glycyrrhizin (2, 4, and 10mg/kg) was administered by intra-articular knee injection for 12weeks. Incapacitance test was performed to determine mechanical hyperalgesia. Enzyme-linked immunosorbent assay (ELISA) was performed to measure cartilage degradation and inflammation-related markers. Quantitative reverse transcription PCR (RT-qPCR) and Western blot were performed to determine the mRNA and protein levels of genes, respectively. The results demonstrated that treatment with glycyrrhizin ameliorated mechanical hyperalgesia and bilateral joints oedema in a rat model of osteoarthritis. Treatment with 10mg/kg glycyrrhizin also suppressed serum enzymes including matrix metalloproteinase (MMP)-1, MMP-3, prostaglandin E2, and C-telopeptide of type II collagen (CTX-II). In addition to inhibition of cartilage matrix catabolic related markers, treatment with glycyrrhizin also decreased the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and iNOS in serum and cartilage. The underlying mechanism study demonstrated that treatment with glycyrrhizin inhibited HMGB1 and the TLR4/NF-κB signaling pathway. In summary, treatment with glycyrrhizin ameliorated cartilage degeneration and inflammation in osteoarthritis rats by the regulation of HMGB1 and the TLR4/NF-κB signaling pathway.

Endogenous anandamide and self-reported pain are significantly reduced after a 2-week multimodal treatment with and without radon therapy in patients with knee osteoarthritis: a pilot study

Multimodal therapies comprising spa applications are widely used as non-pharmaceutical treatment options for musculoskeletal diseases. The purpose of this randomized, controlled, open pilot study was to elucidate the involvement of the endocannabinoid system in a multimodal therapy approach. Twenty-five elderly patients with knee osteoarthritis (OA) received a 2-week spa therapy with or without combination of low-dose radon therapy in the Bad Gastein radon gallery. A 10-point numerical rating scale (pain in motion and at rest), WOMAC questionnaire, and the EuroQol-5D (EQ-5D) questionnaire were recorded at baseline, and during treatment period at weeks one and two, and at 3-month and 6-month follow-ups. Plasma levels of the endocannabinoid anandamide (AEA) were determined at baseline and at 2 weeks, and serum levels of several cartilage metabolism markers at all five time-points. A significant and sustained reduction of self-reported knee pain was observed in the study population, but no further significant effect of the additional radon therapy up and above base therapy. This pain reduction was accompanied by a significant reduction of AEA plasma levels during treatment in both groups. No significant differences were seen in serum marker concentrations between the groups treated with or without radon, but a small reduction of serum cartilage degradation markers was observed during treatment in both groups. This is the first study investigating AEA levels in the context of a non-pharmacological OA treatment. Since the endocannabinoid system represents a potential target for the development of new therapeutics, further studies will have to elucidate its involvement in OA pain.

Obesity Contribution in Synthesis and Degradation of Cartilage Marker Through Inflammation Pathway in Osteoarthritis Patient: Analysis of Adiponectin, Leptin, Ykl-40 and Cartilage Oligomeric Matrix Proteinase (Comp) Synovial Fluid

Background: To determine the role of obesity in osteoarthritis (OA) through inflammation pathway byanalyzing articular cartilage synthesis and degradation markers in synovial fluid.Methods: We performed observational study with cross sectional approach. Obesity was determinedbased on WC. OA genu diagnosed based on American College of Rheumatology (ACR) 1986 criteria. Weexamined leptin as inflammation marker, adiponectin as anti-inflammation marker, YKL-40 as cartilagesynthesis marker and COMP as cartilage degradation marker in synovial joint using ELISA.Results: From 70 OA genu patients, 61 subjects with central obesity and 9 subjects with non-central obesity.In OA patient with central obesity group, WC does not correlate directly with COMP and YKL-40, butthrough level of adiponectin and leptin. WC correlates with adiponectin and leptin level, and then adiponectinlevel correlate with YKL-40 level, and leptin level correlate with COMP level, the greater the WC, the loweradiponectin level and the higher leptin level. The lower the adiponectin level, the lower the YKL-40 leveland the higher the leptin level, the higher the COMP level. Whereas in OA patient with non-central obesitygroup, WC is directly correlated with COMP level (not through adiponectin or leptin); the greater WC, thehigher COMP level. WC does not correlate directly with YKL-40, but through adiponectin due to increasingage, not because of changes in WC. In non-central obesity, the older a person is, the lower adiponectin level;and the lower adiponectin level, the lower YKL-40 level.Conclusions: Obesity contributed in central obese OA, group on destruction of articular cartilage wasdirectly correlated with WC without involving inflammation pathway.

Concerted actions by MMPs, ADAMTS and serine proteases during remodeling of the cartilage callus into bone during osseointegration of hip implants

IntroductionAlthough the number of patients undergoing total hip arthroplasty is constantly on the rise, we only have limited knowledge of the molecular mechanisms necessary for successful osseointegration of implants or the reasons why some fail. Understanding the spatiotemporal characteristics of signaling pathways involved in bone healing of implants is therefore of particular importance for our ability to identify factors causing implants to fail. The current study investigated the role of three families of proteases, i.e. MMPs (matrix metalloproteinases), ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and serine proteases, as well as their endogenous inhibitors during osseointegration of hip implants that have endured two decades of use without clinical or radiological signs of loosening. Materials and methodsTwenty-four patients that had undergone primary THA due to one-sided osteoarthritis (OA) were monitored during 18 years (Y) with repeated measurements of plasma biomarkers, clinical variables and radiographs. All implants were clinically and radiographically well-fixed throughout the follow-up. Eighty-one healthy donors divided in three gender and age-matched groups and twenty OA patients awaiting THA, served as controls. Plasma was analyzed for MMP-1, -2, -3, -8, -9, -10, -13, -14, tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, ADAMTS4, ADAMTS5, the serine proteases neutrophil elastase (NE), proteinase 3 (PR3) and their endogenous inhibitors, secretory leucocyte proteinase inhibitor (SLPI), trappin-2/elafin and serpina1 (α-1 antitrypsin). Cartilage turnover was monitored using two markers of cartilage synthesis, type II procollagen and PIICP (procollagen II C-terminal propeptide), and two markers of cartilage degradation, CTX-II (C-terminal telopeptide fragments of type II collagen) and split products of aggrecan (G1-IGD-G2). ResultsMMP-1, MMP-9, ADAMTS4, NE and PR3 were above healthy in presurgery OA patients but returned to the level of healthy within 6 weeks (W) after surgery. MMPs and serine proteases were counter-regulated during this phase by TIMP-1, SLPI and trappin-2/elafin. Type II procollagen, PIICP and CTX-II increased to a peak 6 W after surgery with a gradual return to the level of controls within weeks. Significant increases by MMP-8, MMP-9, ADAMTS4, ADAMTS5, NE, PR3 and the protease inhibitors, TIMP-3 and serpina1, were seen 5 Y after hip arthroplasty paralleled by a sharp increase in the levels of the cartilage degradation markers, CTX-II and G1-IGD-G2. All the above mediators were normalized before 18 Y, except MMP-1 and MMP-9 that remained above healthy at 18 Y. MMP-14 increased immediately after surgery and remained elevated until 5 Y postsurgery before returning to the level of controls at 7 Y. ConclusionNotwithstanding temporal differences, the molecular processes of bone repair in arthroplasty patients show great spatial similarities with the classical phases of fracture repair as previously shown in animal models. Cartilagenous callus, produced and remodeled early after hip arthroplasty, is replaced with bone 5 Y to7 Y after surgery by the concerted actions of MMP-8, MMP-9, ADAMTS4, ADAMTS5, NE and PR3, thus suggesting that a complex regulatory cross-talk may exist between different families of proteases during this transitional phase of cartilage degradation. Regulation and fine-tuning of cartilage remodeling by MMPs and ADAMTS is controlled by TIMP-3 whereas serine proteases are regulated by serpina1. Increased MMP-1 and MMP-9 beyond 10Y post-THA support a role during coupled bone remodeling.

МАРКЕРИ ОБМІНУ СПОЛУЧНОЇ ТКАНИНИ У ХВОРИХ З ДІАБЕТИЧНИМИ АРТРОПАТІЯМИ

The aim of study was to investigate markers of connective tissue metabolism (COMP level) and indicators that reflect the synthetic and catabolic phases of the metabolism of the main components of connective tissue - collagen and glycosaminoglycans in patients with diabetic arthropathy.The study involved 87 patients with diabetes. Patients were examined using a visual analogue scale of the Leken index and WOMAK. Cartilage oligomeric matrix Protein (COMP) was determined using enzyme immunoassay.Results. The presence of diabetic arthropathy was detected in 78% of patients with type 1 diabetes and in 80% of patients with type 2 diabetes. In the vast majority of patients, the joints of the upper extremities were involved in the pathological process. A direct correlation was established between the presence of arthropathy and the COMP level (r = 0.76, p = 0.001), the Leken index (r = 0.76, p = 0.001), YOUR scale (r = 0.88 , p = 0.001) and WOMAK (R = 0.88, p = 0.001). Patients with type 1 diabetes with joint damage are characterized by a compensatory increase in the synthesis of subchondral bone in response to increased collagen breakdown. For patients with type 1 diabetes with joint damage is characterized by a compensatory increase in subchondral bone synthesis in response to increased collagen breakdown.Conclusions: The results suggest that arthropathy in patients with type 1 and type 2 diabetes is characterized by an increase in the cartilage degradation marker in direct proportion to the severity and number of affected joints.

Anterior cruciate ligament reconstruction reinitiates an inflammatory and chondrodegenerative process in the knee joint.

Anterior cruciate ligament (ACL) injury leads to a sustained increase in synovial fluid concentrations of inflammatory cytokines and biomarkers of cartilage breakdown. While this has been documented post-injury, it remains unclear whether ACL reconstruction surgery contributes to the inflammatory process and/or cartilage breakdown. This study is a secondary analysis of 14 patients (nine males/five females, mean age = 9, mean BMI = 28) enrolled in an IRB-approved randomized clinical trial. Arthrocentesis was performed at initial presentation (mean = 6 days post-injury), immediately prior to surgery (mean = 23 days post-injury), 1-week post-surgery, and 1-month post-surgery. Enzyme-linked immunosorbant assay kits were used to determine concentrations of carboxy-terminal telopeptides of type II collagen (CTXII), interleukin-6 (IL-6), and IL-1β in the synovial fluid. The log-transformed IL-1β was not normally distributed; therefore, changes between time points were evaluated using a non-parametric Kruskal-Wallis one-way ANOVA. IL-1β concentrations significantly increased from the day of surgery to the first postoperative time point (P ≤ .001) and significantly decreased at the 4-week postoperative visit (P = .03). IL-1β concentrations at the 4-week postoperative visit remained significantly greater than both preoperative time points (P > .05). IL-6 concentrations at 1-week post-surgery were significantly higher than at initial presentation (P = .013), the day of surgery (P < .001), and 4 weeks after surgery (P = .002). CTX-II concentrations did not differ between the first three-time points (P > .99) but significantly increased at 4 weeks post-surgery (P < .01). ACL reconstruction appears to reinitiate an inflammatory response followed by an increase in markers for cartilage degradation. ACL reconstruction appears to initiate a second "inflammatory hit" resulting in increased chondral breakdown suggesting that post-operative chondroprotection may be needed.

Eggshell Membrane+Fish Oil Combination (Move3î) Reduces Exercise-Induced Joint Pain, Stiffness and Cartilage Turnover in Healthy Adults: Results from a Randomized, Double-Blind, Placebo-Controlled Study

Background: Eggshell membrane supplementation has been shown to reduce exercise-induced joint pain and stiffness and lower urinary excretion of C-terminal cross-linked telopeptide of type-II collagen (uCTX-II), a marker of cartilage degradation, in healthy, postmenopausal women. This study was conducted to evaluate whether the combination of eggshell membrane and omega-3 polyunsaturated fatty acids (ES-OM3) versus placebo would reduce levels of uCTX-II and alleviate joint pain or stiffness immediately following exercise and 12 hours post exercise in healthy men and women. Methods: The study was a two-week randomized, double-blind, placebo-controlled trial. Eighty-five healthy men and women (40-70 years) were randomly assigned to receive either 500 mg eggshell membrane with 1,500 mg fish oil concentrate (n=43) or 2,000 mg placebo (n=42) daily. Subjects performed an aerobic step exercise regimen (40 to 100 steps per leg) on alternating days. The primary endpoint was any statistically significant reduction in exercise-induced cartilage turnover as determined by levels of uCTX-II versus placebo, evaluated after 1 and 2 weeks of exercise. Secondary endpoints were changes in exercise-induced joint pain or stiffness versus placebo, evaluated immediately after exercise and 12 hours post exercise. Results: ES-OM3 produced a significant reduction in levels of uCTX-II versus placebo after 1 (-12.9%, p=0.035) and 2 weeks of exercise (-17.7%, p=0.019). Compared with placebo, ES-OM3 supplementation significantly relieved joint pain (p<0.05) immediately after exercise and 12 hours after exercise (Days 3,5 and 7 and Days 2 and 8 respectively) and significantly improved levels of stiffness (p<0.05) immediately after exercise and 12 hours after exercise (Day 3, and Days 2,4,6 and 8, respectively). Conclusion: In healthy adults who performed an aerobic step exercise regimen for two weeks, daily administration of a novel nutraceutical (Move3®), consisting of eggshell membrane and fish oil (ES-OM3) decreased levels of CTX-II, a biomarker for cartilage degradation. ES-OM3 supplementation provided rapid relief of joint pain and stiffness immediately after exercise and 12 hours post exercise. Use of a nutraceutical such as ES-OM3 (Move3®) is a promising new approach for alleviating joint pain and stiffness associated with exercise. Trial registration: NCT 04215198

Clinical and biochemical markers of joint damage in patients with diabetes mellitus

The aim of our work was to study the COMP level in the blood serum of patients with type 1 and type 2 diabetes with arthropathy and to determine the relationship with functional indices characterizing the clinical manifestations of joint damage in patients with diabetes mellitus.Materials and methods. The study involved 87 patients (35 men and 52 women) with diabetes. Patients were divided into groups depending on the type of diabetes and the presence of arthropathy. Patients were examined using a visual analogue scale, Lequesne’s index and WOMAC scale. Cartilage oligomeric matrix protein (COMP) was determined by enzyme immunoassay.Results. The presence of diabetic arthropathy was found in 78 % of patients with type 1 diabetes and in 80 % of patients with type 2 diabetes. In the vast majority of patients (20 with type 1 diabetes and 30 with type 2 diabetes), the joints of the upper extremities were involved in the pathological process. We found an increase in functional indices in patients with arthropathy in both types of disease: Lequesne’s index – t = -5.5, P = 0.001 – in patients with type 1 diabetes, t = -6.9, P = 0.001 – in patients with type 2 diabetes, WOMAK index (t = -5.4, P = 0.001), (t = -7.8, P = 0.001); visual analogue scale (t = -6, P = 0.001), (t = -6.9, P = 0.001), respectively. Average COMR values significantly increased with the arthropathy stage progression (t = -3.4, P = 0.005; t = -2.4, P = 0.0023; t = -3.2, P = 0.006) in patients with type 1 diabetes. In patients with type 2 diabetes, the significance of differences was found between the control group and patients with stage 1 (t = 3.4, P = 0.001), between stages 1 and 2 (t = -4.1, P = 0.001). A direct correlation was established between the presence of arthropathy and the COMP level (r = 0.76, P = 0.001), between the presence of arthropathy and the Lequesne’s index (r = 0.76, P = 0.001), the visual analogue scale (r = 0.88, P = 0.001) and WOMAC (R = 0.88, P = 0.001).Conclusions. The results suggest that arthropathy in patients with type 1 and type 2 diabetes is characterized by an increase in the cartilage degradation marker directly related to the severity and the number of joints affected.