Cathepsin g Degrades Both Glycosylated and Unglycosylated Regions of Lubricin, a Synovial Mucin

AbstractLubricin (PRG4) is a mucin type protein that plays an important role in maintaining normal joint function by providing lubrication and chondroprotection. Improper lubricin modification and degradation has been observed in idiopathic osteoarthritis (OA), while the detailed mechanism still remains unknown. We hypothesized that the protease cathepsin G (CG) may participate in degrading lubricin in synovial fluid (SF). The presence of endogenous CG in SF was confirmed in 16 patients with knee OA. Recombinant human lubricin (rhPRG4) and native lubricin purified from the SF of patients were incubated with exogenous CG and lubricin degradation was monitored using western blot, staining by Coomassie or Periodic Acid-Schiff base in gels, and with proteomics. Full length lubricin (∼300 kDa), was efficiently digested with CG generating a 25-kDa protein fragment, originating from the densely glycosylated mucin domain (∼250 kDa). The 25-kDa fragment was present in the SF from OA patients, and the amount was increased after incubation with CG. A CG digest of rhPRG4 revealed 135 peptides and 72 glycopeptides, and confirmed that the protease could cleave in all domains of lubricin, including the mucin domain. Our results suggest that synovial CG may take part in the degradation of lubricin, which could affect the pathological decrease of the lubrication in degenerative joint disease.

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Cathepsin g degrades synovial fluid lubricin: relevance for osteoarthritis pathogenesis

10.1101/792184 ◽

2019 ◽

Cited By ~ 1

Author(s):

Shan Huang ◽

Kristina A. Thomsson ◽

Chunsheng Jin ◽

Sally Alweddi ◽

André Struglics ◽

...

Keyword(s):

Synovial Fluid ◽

Western Blot ◽

Periodic Acid ◽

Full Length ◽

Cathepsin G ◽

Joint Function ◽

Protein Fragment ◽

Periodic Acid Schiff ◽

Detailed Mechanism ◽

Knee Oa

AbstractLubricin (PRG4) is a mucin type protein that plays an important role in maintaining normal joint function by providing lubrication and chondroprotection. Improper lubricin modification and degradation has been observed in idiopathic osteoarthritis (OA), while the detailed mechanism still remains unknown. We hypothesized that the protease cathepsin G (CG) may participate in degrading lubricin in synovial fluid (SF). The presence of endogenous CG in SF was confirmed in 16 patients with knee OA. Recombinant human lubricin (rhPRG4) and native lubricin purified from the SF of patients were incubated with exogenous CG and lubricin degradation was monitored using western blot, staining by Coomassie or Periodic Acid-Schiff in gels, and with proteomics. Full length lubricin (∼300 kDa), was efficiently digested with CG generating a 25-kDa protein fragment, originating from the densely glycosylated mucin domain (∼250 kDa). The 25-kDa fragment was present in the SF from OA patients, and the amount was increased after incubation with CG. A CG digest of rhPRG4 revealed 135 peptides and 72 glycopeptides, and confirmed that the protease could cleave in different domains of lubricin. Our results suggest that synovial CG may take part in the degradation of lubricin, which could affect the lubrication of OA joints.

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Frictional Characteristics and Tissue Loss of Articular Cartilage Under a Novel Wear Regime

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176620 ◽

2007 ◽

Cited By ~ 1

Author(s):

Kelly J. Shields ◽

John R. Owen ◽

Jennifer S. Wayne

Keyword(s):

Articular Cartilage ◽

Articular Surface ◽

Cartilage Damage ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Tissue Loss ◽

Joint Function ◽

Repair Technique ◽

Repair Techniques

Degenerative joint disease, age, and trauma lead to progressive articular cartilage damage due to the tissue’s limited repair capabilities. Numerous clinical repair techniques with varying degrees of success have been developed in order to repair damaged tissue and restore joint function. One approach is the development of articular cartilage repair tissue to implant into the damaged or diseased articular surface. Determining the viability of an articular repair technique or tissue under in vivo stresses and wear is crucial to predict its success.

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Serum Metabolites as Potential Biomarkers for Diagnosis of Knee Osteoarthritis

Disease Markers ◽

10.1155/2015/684794 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 13

Author(s):

Qingmeng Zhang ◽

Heng Li ◽

Zhendong Zhang ◽

Fan Yang ◽

Jiying Chen

Keyword(s):

Knee Osteoarthritis ◽

Metabolic Profile ◽

Elderly Population ◽

The Elderly ◽

Ultra Performance Liquid Chromatography ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Healthy Controls ◽

Knee Oa ◽

Potential Biomarkers

Knee osteoarthritis (OA) is a highly prevalent chronic degenerative joint disease that mainly affects the elderly population. The aim of this study was to investigate serum signature metabolites as potential biomarkers for early diagnosis of knee OA. Global serum metabolic profiles of 40 patients with knee OA and 20 healthy controls (HC) were analyzed by ultra-performance liquid chromatography coupled to mass spectrometry. An OA-specific metabolic profile was established that can clearly discriminate patients with OA from HCs. Fourteen metabolites that are involved in the metabolism of amino acids, purine, energy, glycolysis, fatty acids, and lipids were significantly altered in patients with OA compared to HCs. These metabolites could be potentially used as biomarkers for the diagnosis of knee OA.

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Combined therapies with exercise, ozone and mesenchymal stem cells improve the expression of HIF1 and SOX9 in the cartilage tissue of rats with knee osteoarthritis

Physiology International ◽

10.1556/2060.2020.00024 ◽

2020 ◽

Vol 107 (2) ◽

pp. 231-242

Author(s):

Sara Asadi ◽

Parvin Farzanegi ◽

Mohammad Ali Azarbayjani

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Knee Osteoarthritis ◽

Combined Therapy ◽

Hypoxia Inducible Factor ◽

Degenerative Joint Disease ◽

Exercise Group ◽

Joint Disease ◽

Cartilage Tissue ◽

Knee Oa

AbstractPurposeKnee osteoarthritis (OA) is a common type of degenerative joint disease which decreases the quality of life. Sex-determining region Y box 9 (SOX9) and hypoxia-inducible factor-1 (HIF1) are considered as the key regulators of OA. We investigated the effect of combined therapies with mesenchymal stem cells (MSCs), ozone (O3) and exercise training on SOX9 and HIF1 expression in the cartilage of rats with knee OA.MethodsKnee OA was induced by surgical method. OA rats were divided into model, MSCs, ozone, exercise, MSCs + ozone, MSCs + exercise, ozone + exercise and MSCs + ozone + exercise groups. Rats in the MSCs group received intraarticular injection of 1 × 106 cells/kg. Rats in the ozone group received O3 at the concentration of 20 μg/mL, once weekly for 3 weeks. Rats in the exercise group were trained on rodent treadmill three times per week. 48 hours after the programs, cartilage tissues were isolated and the expression of SOX9 and HIF1 was determined using Real-Time PCR.ResultsSignificant differences were found in the expression of SOX9 and HIF1 between groups (P < 0.0001). Although combined therapies with exercise, MSCs and O3 significantly increased the expression of SOX9 and HIF1 in the cartilage tissue of rats with knee OA, combination of exercise with O3 was significantly more effective compared to the other combined therapies (P < 0.001).ConclusionsCombined therapy with exercise, MSCs and O3 significantly increased the expression of SOX9 and HIF1 genes in the cartilage of rats with knee OA; however, exercise + O3 was significantly more effective.

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In vivo acute toxicity and anti-gastric evaluation of a novel dichloro Schiff base: Bax and HSP70 alteration

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz140 ◽

2019 ◽

Vol 52 (1) ◽

pp. 26-37

Author(s):

Kamelia Saremi ◽

Sima Kianpour Rad ◽

Maryam Khalilzadeh ◽

Jamal Hussaini ◽

Nazia Abdul Majid

Keyword(s):

Antioxidant Activity ◽

Schiff Base ◽

Periodic Acid ◽

Gastric Wall ◽

Schiff Base Complex ◽

Periodic Acid Schiff ◽

Over Expression ◽

Bax Protein ◽

Sd Rats

Abstract Chlorine is shown to possess anti-gastric ulcer activity, since it can inactivate Helicobacter pylori, which is regarded as one of the most common risk factors for causing gastric problems. In the current study, the gastroprotective property of a novel dichloro-substituted Schiff base complex, 2, 2′- [−1, 2-cyclohexanediylbis(nitriloethylidyne)] bis(4-chlorophenol) (CNCP), against alcohol-induced gastric lesion in SD rats was assessed. SD rats were divided into four groups, i.e. normal, ulcer control, testing, and reference groups. Ulcer area, gastric wall mucus, and also gastric acidity of the animal stomachs were measured. In addition, antioxidant activity of CNCP was evaluated and its safe dose was identified. Immunohistochemistry staining was also carried to evaluate two important proteins, i.e. Bcl2-associated X protein (Bax) and heat shock protein 70 (HSP70). Moreover, the activities of super oxide dismutase and catalase, as well as the levels of prostaglandin E2 (PGE2) and malondialdehyde (MDA) were also measured. Antioxidant activity of CNCP was approved via the aforementioned experiments. Histological evaluations showed that the compound possesses stomach epithelial defense activity. Additionally, periodic acid-Schiff staining exhibited over-expression of HSP70 and down-expression of Bax protein in the CNCP-treated rats. Moreover, CNCP caused deceased MDA level and elevated PGE2 level, and at the same time increased the activities of the two enzymes.

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Systemic versus local adipokine expression differs in a combined obesity and osteoarthritis mouse model

Scientific Reports ◽

10.1038/s41598-021-96545-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marie-Lisa Hülser ◽

Yubin Luo ◽

Klaus Frommer ◽

Rebecca Hasseli ◽

Kernt Köhler ◽

...

Keyword(s):

High Fat Diet ◽

Medial Meniscus ◽

Degenerative Joint Disease ◽

Mechanisms Of Action ◽

Normal Diet ◽

Joint Disease ◽

Metabolic Effects ◽

High Fat ◽

Joint Function ◽

Diet Induced Obesity

AbstractOsteoarthritis (OA) is a degenerative joint disease characterized by cartilage loss and reduced joint function. OA risk factors are age and obesity. Many adipokines are altered by obesity but also OA although systemic adipokine regulation in OA is not always clear. Therefore, metabolic effects of diet-induced obesity on OA development as well as the influence of obesity and OA progression on systemic vs. local adipokine expression in joints were compared. C57Bl/6-mice fed with HFD (high fat diet) or normal diet prior to destabilization of the medial meniscus (DMM) were sacrificed 4/6/8 weeks after surgery. Sera were evaluated for adiponectin, leptin, visfatin, cytokines. Liver grading and staging for non-alcoholic steatohepatitis (NASH) was performed and crown-like structures (CLS) in adipose tissue measured. OA progression was scored histologically. Adipokine-expressing cells and types were evaluated by immunohistochemistry. Time-dependent changes in DMM-progression were reflected by increased systemic adiponectin levels in DMM especially combined with HFD. While HFD increased serum leptin, DMM reduced systemic leptin significantly. OA scores correlated with bodyweight, leptin and hepatic scoring. Locally, increased numbers of adiponectin- and leptin-producing fibroblasts were observed in damaged menisci but visfatin was not changed. Local adipokine expression was independent from systemic levels, suggesting different mechanisms of action.

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Efficacy of intra-articular injection of combined platelet-rich plasma and hyaluronic acid in knee degenerative joint disease (182)

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967121s00300 ◽

2021 ◽

Vol 9 (10_suppl5) ◽

pp. 2325967121S0030

Author(s):

Pietro Randelli ◽

FILIPPO RANDELLI ◽

Fabio Sciancalepore ◽

Chiara Fossati ◽

Stefano Pasqualotto ◽

...

Keyword(s):

Hyaluronic Acid ◽

Conservative Treatment ◽

Current Literature ◽

Platelet Rich Plasma ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Knee Oa ◽

Significant Difference ◽

Early Oa

Objectives: Osteoarthritis (OA) of the knee is a debilitating disease whose prevalence has increased across the world with aging population. Platelet-Rich Plasma (PRP) and Hyaluronic Acid (HA) injections appear to be two of the main strategies for conservative treatment of early knee OA. The effectiveness of both treatments, however, is still under debate because contrasting results have been described in the current literature. Some pre-clinical studies evaluated the association of PRP and HA with encouraging results, highlighting the possibility of a synergistic effect between the two compounds and suggesting a possible use through combined intra-articular injections. The aim of this prospective randomized controlled double-blind clinical trial is to evaluate the efficacy of intra-articular injections of PRP and HA for the treatment of early stages of knee degenerative joint disease in improving joint function and reducing pain, compared to the intra-articular injections of PRP and HA alone. Methods: Patients with knee early OA were prospectively enrolled and then double-blinded randomly divided into three groups of fifty-eight subjects each: HA alone, PRP alone and PRP+HA group. Patients received three intra-articular injections with two-week interval period among each dose. Patients clinical outcome was evaluated through five questionnaires [The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Tegner Activity, Visual Analogue Scale (VAS), Knee injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC) Subjective Knee Form] before the treatment (T0) and after 3, 6 and 12 months from the first injection. Patients’use of paracetamol and supplementary analgesia for knee pain during the study was collected. Results: One hundred and seventy-four patients were enrolled in this study (age, 30-80 years; 108 females and 66 males) and 162 completed the 12-month follow-up. All patients showed significant clinical improvement after treatment. The analysis of covariance (ANCOVA) did not show statistically significant differences among the three groups for all the variables analysed at 6 and 12 months of follow-up (p>0.05).No significant differences were found in terms of adverse events (p=0.49) among the three groups of patients (p=0.92).The demand for paracetamol and supplementary analgesics was generally low and there were no significant differences among the groups (p=0.23 and p=0.56, respectively). Conclusions: Injections treatments for early knee OA are an important conservative therapeutic strategy. To date, the current literature presents many contrasting studies about the effectiveness of PRP or HA, but only a few consider the combined use of PRP and HA as attractive therapeutic option. Our study has not shown any significant difference in clinical and functional outcomes among the three experimental groups, suggesting a substantial equivalence of these three treatments. Thus, cost-effectiveness is in favor of HA injections in the conservative treatment of early OA.

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From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside

International Journal of Molecular Sciences ◽

10.3390/ijms22052697 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2697

Author(s):

Elena Rezuş ◽

Alexandra Burlui ◽

Anca Cardoneanu ◽

Luana Andreea Macovei ◽

Bogdan Ionel Tamba ◽

...

Keyword(s):

Treatment Plan ◽

Weight Bearing ◽

Unmet Need ◽

High Body Mass Index ◽

Joint Disease ◽

Sufficient Evidence ◽

Joint Function ◽

Knee Oa ◽

Bone Changes ◽

Disease Modifying

Osteoarthritis (OA) is currently the most widespread musculoskeletal condition and primarily affects weight-bearing joints such as the knees and hips. Importantly, knee OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathomechanisms. Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis. However, the pathogenic intricacies between the molecular pathways involved in OA prompted the study of certain drugs for more than one therapeutic target (amelioration of cartilage and bone changes, and synovial inflammation). Most clinical studies regarding knee OA focus mainly on improvement in pain and joint function and thus do not provide sufficient evidence on the possible disease-modifying properties of the tested drugs. Currently, there is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for these patients.

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Treatment and Prevention of Osteoarthritis through Exercise and Sports

Journal of Aging Research ◽

10.4061/2011/374653 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 21

Author(s):

Victor Valderrabano ◽

Christina Steiger

Keyword(s):

Pain Relief ◽

Muscle Function ◽

Symptomatic Treatment ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Joint Function ◽

Treatment And Prevention ◽

High Prevalence ◽

Strengthening Exercises ◽

Prevention And Treatment

Osteoarthritis (OA) is a degenerative joint disease with a high prevalence among older people. To date, the pathogenesis of the disease and the link between muscle function and OA is not entirely understood. As there is no known cure for OA, current research focuses on prevention and symptomatic treatment of the disorder. Recent research has indicated that muscle weakness precedes the onset of OA symptoms. Furthermore, several studies show a beneficial effect of land-based aerobic and strengthening exercises on pain relief and joint function. Therefore, current research focuses on the possibility to employ exercise and sports in the prevention and treatment of OA.

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An evolutionary perspective of DNA methylation patterns in skeletal tissues using a nonhuman primate model of osteoarthritis

10.1101/2020.07.31.231522 ◽

2020 ◽

Author(s):

Genevieve Housman ◽

Ellen E. Quillen ◽

Anne C. Stone

Keyword(s):

Dna Methylation ◽

Nonhuman Primate ◽

Molecular Mechanisms ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Evolutionary Perspective ◽

Nonhuman Primate Model ◽

Primate Model ◽

Knee Oa ◽

Methylation Patterns

AbstractObjectiveEpigenetic factors, such as DNA methylation, play an influential role in the development of the degenerative joint disease osteoarthritis (OA). These molecular mechanisms have been heavily studied in humans, and although OA affects several other animals in addition to humans, few efforts have taken an evolutionary perspective. This study explores the evolution of OA epigenetics by assessing the relationship between DNA methylation variation and knee OA development in baboons (Papio spp.) and by comparing these findings to human OA epigenetic associations.MethodsGenome-wide DNA methylation patterns were identified in bone and cartilage of the right distal femora from 56 pedigreed, adult baboons (28 with and 28 without knee OA) using the Illumina Infinium MethylationEPIC BeadChip.ResultsSeveral significantly differentially methylated positions (DMPs) and regions (DMRs) were found between tissue types. Substantial OA-related differential methylation was also identified in cartilage, but not in bone, suggesting that cartilage epigenetics may be more influential in OA than bone epigenetics. Additionally, some genes containing OA-related DMPs overlap with and display methylation patterns similar to those previously identified in human OA, revealing a mixture of evolutionarily conserved and divergent OA-related methylation patterns in primates.ConclusionsOverall, these findings reinforce current etiological perspectives of OA and enhance our evolutionary understanding of epigenetic mechanisms associated with OA. This work further establishes baboons as a valuable nonhuman primate model of OA, and continued investigations in baboons will help to disentangle the molecular mechanisms contributing to OA and their evolutionary histories.

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