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Protective Effects of Many Citrus Flavonoids on Cartilage Degradation Process  [PDF]
Lucia Crascì, Annamaria Panico
Journal of Biomaterials and Nanobiotechnology (JBNB) , 2013, DOI: 10.4236/jbnb.2013.43035
Abstract: The objective of this study was to investigate the effects of many citrus flavanones, such as neoeriocitrin, naringin and neohesperidin, in cartilage degradation. Degenerative joint disease involved degradation of joints, including articular cartilage and subchondral bone. When bone surfaces become less well protected by cartilage, bone may be exposed and damaged. The degradation cartilage is mediated by alteration of the balance between anabolic and catabolic processes, changes in proteolytic enzyme activity, mechanical disruption of the cartilage extracellular matrix (ECM), or a combination of these processes. We examine the capability of neoeriocitrin, naringin and neohesperidin, to inhibit metalloproteinase (MMP)-13, collagenase involved in degradation of cartilage matrix components. Also, we assay the flavonoids effect on reducing of Glycosaminoglycans (GAGs) release, and restore Nitric oxide (NO) levels in explant of human articular cartilage. Our results suggest that neoeriocitrin, naringin and neohesperidin are a potential therapeutic agent to protect cartilage tissue.
Sonochemical Effects on 14 Flavonoids Common in Citrus: Relation to Stability  [PDF]
Liping Qiao, Yujing Sun, Rongrong Chen, Yu Fu, Wenjuan Zhang, Xin Li, Jianchu Chen, Yan Shen, Xingqian Ye
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087766
Abstract: The sonochemical effects of ultrasound (US) treatment on 14 flavonoids representing the main flavonoids in citrus fruit were investigated in a standard mixture by stability evaluation of a model system. Degradation products were further tentatively identified by Fourier transform infrared spectroscopy and high-performance liquid chromatography–ultraviolet detection–electrospray ionization tandem mass spectrometry. Thirteen flavonoids (i.e., eriocitrin, narirutin, neohesperidin, quercitrin, eridictyol, didymin, naringenin, luteolin, sinensetin, nobiletin, tangeretin, naringin, and hesperidin) were fairly stable whereas quercetin was degraded significantly by US treatment. The types of solvent and temperature used were important factors that determined the resulting degradation reactions. The degradation rate of quercetin was highest in 80% ethanol aqueous solution and decreased with increasing temperature. Longer US durations caused increases in the extent of quercetin degradation. Liquid height, ultrasonic intensity, pulse length, and duty cycle of US affected degradation rates but did not change the nature of degradation of the flavonoids. Four types of reactions occurred simultaneously for quercetin under US treatment: oxidation, addition, polymerization, and decomposition. Eight degradation products were tentatively identified as dimer, alcohol addition, oxidation, and decomposition products.
Aggrecanases and cartilage matrix degradation
Hideaki Nagase, Masahide Kashiwagi
Arthritis Research & Therapy , 2003, DOI: 10.1186/ar630
Abstract: Cartilage consists of a relatively small number of chondrocytes and abundant extracellular matrix (ECM) components. While numerous macromolecules have been identified in cartilage, the major constituents are collagen fibrils and aggrecan, a large aggregating proteoglycan [1]. Collagen fibrils consisting mainly of type II collagen and, to a lesser extent, of collagen type IX and type XI form an oriented meshwork that provides the cartilage with tensile strength. Aggrecans fill the interstices of the collagen meshwork by forming large aggregated complexes interacting with hyaluronan and link proteins. Aggrecan monomers are approximately 2.5 million Da and consist of a 250-kDa core protein to which chondroitin sulfate and keratan sulfate glycosaminoglycan (GAG) chains are covalently attached. Aggrecans are highly hydrated because of their negatively charged long polysaccharide chains, and thus provide the cartilage with its ability to resist compressive loads.Chondrocytes synthesize and catabolize ECM macromolecules, while the matrix in turn functions to maintain the homeostasis of the cellular environment and the structure of cartilage. In diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA), degradation of the ECM exceeds its synthesis, resulting in a net decrease in the amount of cartilage matrix or even in the complete erosion of the cartilage overlying the bone at the joint surface. Although many possible causes of cartilage destruction have been suggested, such as hypoxic conditions and oxygen-derived free radicals [2,3], the primary cause of this process is thought to be an elevation in the activities of proteolytic enzymes. The loss of aggrecan is considered a critical early event of arthritis, occurring initially at the joint surface and progressing to the deeper zones. This is followed by degradation of collagen fibrils and mechanical failure of the tissue.The matrix metalloproteinases (MMPs) have been considered the main enzymes responsible for
Developmental Mechanisms in Articular Cartilage Degradation in Osteoarthritis  [PDF]
Elena V. Tchetina
Arthritis , 2011, DOI: 10.1155/2011/683970
Abstract: Osteoarthritis is the most common arthritic condition, which involves progressive degeneration of articular cartilage. The most recent accomplishments have significantly advanced our understanding on the mechanisms of the disease development and progression. The most intriguing is the growing evidence indicating that extracellular matrix destruction in osteoarthritic articular cartilage resembles that in the hypertrophic zone of fetal growth plate during endochondral ossification. This suggests common regulatory mechanisms of matrix degradation in OA and in the development and can provide new approaches for the treatment of the disease by targeting reparation of chondrocyte phenotype.
Articular cartilage and changes in Arthritis: Matrix degradation
John S Mort, Caron J Billington
Arthritis Research & Therapy , 2001, DOI: 10.1186/ar325
Abstract: Destruction of articular cartilage is an irreversible consequence of arthritis. Cartilage consists of two major components, a type-II-collagen-fibril network with associated small proteoglycans, and proteoglycan aggregates composed of a noncovalent association between aggrecan, hyaluronate, and link protein. In arthritis, proteoglycan degradation is thought to be an early and reversible process, whereas the breakdown of the collagen network is believed to be irreversible, contributing to loss of joint function. While free radical attack and the action of glycosidases may play a role in cartilage deterioration, the most important degradative agents are proteolytic enzymes.Proteolytic cleavage of the major components of the cartilage extracellular matrix is effected by a number of proteases, many of which are synthesized by chondrocytes and synovial cells in response to inflammatory stimuli. Members of each of the four classes of protease – serine/threonine proteases, cysteine proteases, aspartic proteases, and metalloproteases – have been implicated in the degradation of cartilage. However, current data indicate that the initial steps in matrix breakdown are extracellular processes involving metalloproteases. This class of enzyme is characterized by the presence, within the active site, of a metal ion (usually zinc), which is required for catalytic activity. Of the metalloproteases, the members of two families, the matrix metalloproteases (MMPs) and the ADAMTSs (a disintegrin and a metalloprotease with thrombospondin motifs) family, have been implicated in the breakdown of collagen and aggrecan, respectively. These enzymes are members of the M10 and M12 peptidase families as classified in the universal protease database, MEROPS [1].Cleavage of peptide bonds is a very simple chemical reaction and many proteolytic enzymes are relatively small proteins (~30 kDa) consisting simply of a binding site to accommodate about six amino acid residues of the substrate and the cat
Developmental Mechanisms in Articular Cartilage Degradation in Osteoarthritis  [PDF]
Elena V. Tchetina
Arthritis , 2011, DOI: 10.1155/2011/683970
Abstract: Osteoarthritis is the most common arthritic condition, which involves progressive degeneration of articular cartilage. The most recent accomplishments have significantly advanced our understanding on the mechanisms of the disease development and progression. The most intriguing is the growing evidence indicating that extracellular matrix destruction in osteoarthritic articular cartilage resembles that in the hypertrophic zone of fetal growth plate during endochondral ossification. This suggests common regulatory mechanisms of matrix degradation in OA and in the development and can provide new approaches for the treatment of the disease by targeting reparation of chondrocyte phenotype. 1. Introduction Osteoarthritis (OA) is the most common joint disease, which is associated with a risk of mobility disability. It affects approximately 12% of the aging Western population, while a quarter of people aged over 55 have an episode of persistent knee pain [1]. The pathology of OA involves the whole joint and is associated with focal and progressive hyaline articular cartilage loss, concomitant sclerotic changes in the subchondral bone, and the development of osteophytes. Soft tissue structures in and around the joint including synovium, ligaments, and muscles are also involved [2]. OA affects predominantly articular cartilage, which degrades by gradual loss of its extracellular matrix (ECM) composed mainly of aggrecan and type II collagen. Loss of large proteoglycan aggrecan decreases cartilage compressive stiffness and precedes the damage to collagen fibrillar network, which is responsible for tensile properties of the tissue [3]. Aggrecan degradation is associated with upregulation of aggrecanases a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS-) 4 and 5 as well as matrix metalloproteinases (MMPs) [4]. The excessive cleavage of type II collagen in OA is assumed to be caused by the upregulation of the synthesis and activities of collagenases [5–7], in particular MMP-13 [8–10]. Presently, it is believed that articular cartilage destruction in OA results from excessive loading, age-related changes, and metabolic imbalance in the tissue [11–13]. OA also exhibits features of a systemic disease as it has been shown to involve vascular pathology [14, 15] as well as T-cell immune response [16, 17] associated with upregulation of cytokines such as interleukin (IL-) β and tumor necrosis factor (TNF)α [3, 18], which aggravate cartilage resorption [19]. As the mechanism of OA development is not completely understood, the disease manifestations, which
Comparison of glucose derivatives effects on cartilage degradation
Thanyaluck Phitak, Peraphan Pothacharoen, Prachya Kongtawelert
BMC Musculoskeletal Disorders , 2010, DOI: 10.1186/1471-2474-11-162
Abstract: Porcine cartilage explants were co-cultured with recombinant human IL-1β and each tested substance for 3 days. HA, s-GAG and MMP-2 releases to media were measured using ELISA, dye-binding assay and gelatin zymography, respectively. Similar studies were performed in a human articular chondrocytes (HAC) monolayer culture, where cells were co-treated with IL-1β and each reagent for 24 hours. Subsequently, cells were harvested and gene expression measured using RT-PCR. All experiments were carried out in triplicate. Student's t-tests were used for statistical analysis.In cartilage explants treated with IL-1β, GlcN-S had the highest chondroprotective activity of all four chemicals as shown by the inhibition of HA, s-GAG and MMP-2 released from cartilage. The anabolic (aggrecan core protein; AGG, SOX9) and catabolic (MMP-3, -13) genes in HACs treated with IL-1β and with/without chemicals were studied using RT-PCR. It was found that, GlcN-HCl and GlcN-S could reduce the expression of both MMP-3 and -13 genes. The IL-1β induced-MMP-13 gene expression was decreased maximally by GlcN-S, while the reduction of induced-MMP-3 gene expression was greatest with GlcN-HCl. Glc and GlcA reversed the effect of IL-1β on the expression of AGG and SOX9, but other substances had no effect.This study shows that glucosamine derivatives can alter anabolic and catabolic processes in HACs induced by IL-1β. GlcN-S and GluN-HCl decreased induced MMP-3 and -13 expressions, while Glc and GlcA increased reduced-AGG and SOX9 expression. The chondroprotective study using porcine cartilage explant showed that GlcN-S had the strongest effect.Osteoarthritis (OA) is the most common form of arthritis, and is a public health problem throughout the world. OA is characterized by cartilage deterioration, as evidenced by quantitative and qualitative modification of proteoglycans (PGs) and collagen. An imbalance between the biosynthesis and the degradation of matrix components leads to a progressive destruction
Response to 'Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways'
Cengiz Korkmaz
Arthritis Research & Therapy , 2012, DOI: 10.1186/ar3862
Abstract: I read with great interest Koskinen and colleagues' article about the role of adiponectin on cartilage degradation in OA [1]. The authors showed that plasma adiponectin levels and adiponectin released from OA cartilage were higher in patients with the radiographically more severe OA. They suggested that adiponectin is associated with cartilage destruction in OA [1]. Making an extrapolation based on a cross-sectional study in order to account for the mechanism of cartilage degradation in OA, however, may not be very accurate.Chondrocytes are often believed to exhibit aberrant behaviour and shift to other phenotypes such as anabolic, catabolic or hypertrophic phenotypes over the course of the disease, upon physiological and mechanical stress [2]. The level of biochemical markers and mediators involved in the OA process differ for each one of these phases [3]. Some of these mediators are directly involved in the progression of the OA process or they may be secondary changes in the course of OA. Koskinen and colleagues showed that plasma adiponectin levels were higher in patients with grade IV and V disease than those in patients with grade I, II and III disease (Ahlback classification) [1]. It is my belief that these results do not lead us to conclude that adiponectin could be accountable for degradation of the cartilage. Rather, increased levels of adiponectin may be a secondary phenomenon to the late stage of OA, which could be deemed an indication of severity. Another explanation could be that increased levels of adiponectin may serve as a protective response to the catabolic process in OA. The current understanding of cytokines and growth factors has been shown incapable of determining a single factor that could be responsible for all chondrocyte responses [3].Another point to be raised in this study would be the effect of adiponectin on OA cartilage and primary chondrocytes in vitro. Koskinen and colleagues reported that adiponectin enhanced nitric oxide, IL-6, ma
Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity
Morten A Karsdal, Suzi H Madsen, Claus Christiansen, Kim Henriksen, Amanda J Fosang, Bodil C Sondergaard
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2434
Abstract: Cartilage degradation was induced by oncostatin M and tumour necrosis factor in articular cartilage explants for 7, 11, or 17 days. The catabolic period was followed by 2 weeks of anabolic stimulation (insulin growth factor-I). Cartilage formation was assessed by collagen type II formation (PIINP). Cartilage degradation was measured by matrix metalloproteinase (MMP) mediated type II collagen degradation (CTX-II), and MMP and aggrecanase mediated aggrecan degradation by detecting the 342FFGVG and 374ARGSV neoepitopes. Proteoglycan turnover, content, and localization were assessed by Alcian blue.Catabolic stimulation resulted in increased levels of cartilage degradation, with maximal levels of 374ARGSV (20-fold induction), CTX-II (150-fold induction), and 342FFGVG (30-fold induction) (P < 0.01). Highly distinct protease activities were found with aggrecanase-mediated aggrecan degradation at early stages, whereas MMP-mediated aggrecan and collagen degradation occurred during later stages. Anabolic treatment increased proteoglycan content at all time points (maximally, 250%; P < 0.001). By histology, we found a complete replenishment of glycosaminoglycan at early time points and pericellular localization at an intermediate time point. In contrast, only significantly increased collagen type II formation (200%; P < 0.01) was observed at early time points.Cartilage degradation was completely reversible in the presence of high levels of aggrecanase-mediated aggrecan degradation. After induction of MMP-mediated aggrecan and collagen type II degradation, the chondrocytes had impaired repair capacity.Osteoarthritis (OA) most likely results from altered biomechanical stress that leads to alterations in chondrocyte metabolism [1]. Cartilage turnover may be a more dynamic process than traditionally thought, with continuous remodeling of both the collagen and proteoglycan components of the articular matrix [2], although proteoglycans under physiological conditions may be more remo
Tibolone inhibits bone resorption without secondary positive effects on cartilage degradation
MA Karsdal, I Byrjalsen, DJ Leeming, C Christiansen
BMC Musculoskeletal Disorders , 2008, DOI: 10.1186/1471-2474-9-153
Abstract: This study was a secondary analysis of ninety-one healthy postmenopausal women aged 52–75 yrs entered a 2-yr double blind, randomized, placebo-controlled study of treatment with either 1.25 mg/day (n = 36), or 2.5 mg/day Tibolone (n = 35), or placebo (n = 20), (J Clin Endocrinol Metab. 1996 Jul;81(7):2419–22) Second void morning urine samples were collected at baseline, and at 3, 6, 12, and 24 months. Urine CrossLaps? ELISA (CTX-I) and Urine CartiLaps? ELISA (CTX-II) was investigated as markers of bone resorption and cartilage degradation, respectively.Tibolone significantly (P < 0.001) suppressed bone resorption by approximately 60%. In contrast, no effect was observed on cartilage degradation.These data suggest uncoupling of the bone and cartilage effects of the synthetic steroid, Tibolone. Bone resorption was significantly decreased, whereas cartilage degradation was unchanged. These effects are in contrast to those observed some SERMs with effects on both bone and cartilage degradation. These effects may in part be described by the complicated pharmacology of Tibolone on testosterone, estrogen and progesterone receptors.Osteoarthritis (OA) is the most common form of arthritis [1]. One hallmark of the disease is progressive degeneration of articular cartilage, generation of osteophytes and subsequent joint space narrowing. This progression of disease may involve both bone and cartilage parameters, which in some instances may be tightly coupled.The relationship between bone and cartilage degradation in OA is a complex. A apparent co-existence between the two processes exists [2,3], although the cellular and molecular mechanism remains to be further investigated and identified [4]. Several groups have demonstrated an accelerated incidence of OA in women following menopause [5,6] which in part may be caused by increased bone resorption [7,8]. Studies investigating gender and age as risk factors of developing OA indicate that OA increases with age and women are at a
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