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Prostaglandin PGE2 at very low concentrations suppresses collagen cleavage in cultured human osteoarthritic articular cartilage: this involves a decrease in expression of proinflammatory genes, collagenases and COL10A1, a gene linked to chondrocyte hypertrophy
Elena V Tchetina, John A Di Battista, David J Zukor, John Antoniou, A Robin Poole
Arthritis Research & Therapy , 2007, DOI: 10.1186/ar2273
Abstract: Osteoarthritis (OA) is a systemic condition that can affect single or multiple joints and involves degenerative changes in the articular cartilage, remodeling of subchondral bone and limited synovial inflammation [1]. Osteoarthritic changes in articular cartilage involve progressive proteolytic degradation of its extracellular matrix, composed mainly of type II collagen (COL2A1) and aggrecan, eventually leading to a loss of the cartilage. This involves phenotypic hypertrophy-related changes in chondrocytes, such as the production of type X collagen (COL10A1) (hypertrophy marker), and the upregulation of collagenase matrix metalloproteinase (MMP)-13, as is seen in the fetal growth plate [1-3].Joint inflammation in OA causes an increased synthesis of cyclooxygenase (COX)-2-dependent prostaglandins (PGs), which sensitize peripheral nociceptor terminals and produce localized sensitivity to pain [4]. Non-steroidal anti-inflammatory drugs and specific COX-2 inhibitors are therefore most widely used as painkillers to inhibit prostaglandin production by COX. Prostaglandins, especially PGE2, the major PG synthesized by cartilage [5], are spontaneously released by OA cartilages in amounts 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage stimulated by cytokines [6]. Strong upregulation of COX-2 expression in arthritic synovial membranes and cartilage has led to the suggestion that the selective inhibition of COX-2 may result in an amelioration of arthritic conditions [7].However, PGE2, generated by chondrocytes, has been shown to be physiologically important for maintaining cartilage homeostasis [6]. Because COX-2 is expressed physiologically in some tissues such as glomeruli and cortex, it may have an anti-inflammatory effect [4,8]. It can be protective in OA articular cartilage because it inhibits the expression of IL-1β-induced collagenase and stromelysin in human and animal synovial fibroblasts [9,10], and stimulates collagen and proteogl
Articular cartilage and changes in Arthritis: Collagen of articular cartilage
David Eyre
Arthritis Research & Therapy , 2001, DOI: 10.1186/ar380
Abstract: Collagen accounts for about two-thirds of the dry weight of adult articular cartilage. The tissue's material strength depends on the extensive cross-linking of the collagen and the apparent zonal changes in fibrillar architecture with tissue depth. Once laid down during development, there appears to be little capacity for articular chondrocytes to recapitulate the overall collagen architecture if the mature tissue is injured or undergoes advanced degenerative changes. The ability of chondrocytes to remodel the collagen at ultrastructural and molecular levels is poorly understood, but it may be more significant than previously thought and possible molecular mechanisms are a topic of growing interest.The four zones of articular cartilage visible by light microscopy (superficial or tangential, intermediate or transitional, deep or radial, and calcified) differ in their collagen fibril orientation [1]. In general, collagen fibrils seen by transmission electron microscopy (TEM) (Fig. 1) form a random network compared with those of other connective tissues but, both macroscopically and ultrastructurally, preferred fibril patterns are evident [2]. In the superficial zone (~200 μm), the fibrils are thin and tend to run primarily parallel to the plane of the articular surface with some degree of parallel orientation in that plane. A greater range of fibril diameters is seen in the deeper zones, and the organization appears more random when viewed by TEM. In the radial zone of some joint regions, a preferred orientation of fibril bundles orthogonal to the surface can be seen by scanning electron microscopy, also visible by TEM in regions of pathologically softened cartilage [2]. The arcade-like macro-architecture of collagen responsible for this zonal appearance described by Benninghoff [3] appears, on scanning electron microscopy, to reflect a folding over of radial fiber bundles to lie in the plane of the surface in a series of layers or leaflets that makes up the tangentia
Articular cartilage collagen: an irreplaceable framework?  [PDF]
D R Eyre,M A Weis,J-J Wu
European Cells and Materials (ECM) , 2006,
Abstract: Adult articular cartilage by dry weight is two-thirds collagen. The collagen has a unique molecular phenotype. The nascent type II collagen fibril is a heteropolymer, with collagen IX molecules covalently linked to the surface and collagen XI forming the filamentous template of the fibril as a whole. The functions of collagens IX and XI in the heteropolymer are far from clear but, evidently, they are critically important since mutations in COLIX and COLXI genes can result in chondrodysplasia syndromes. Here we review what is known of the collagen assembly and present new evidence that collagen type III becomes covalently added to the polymeric fabric of adult human articular cartilage, perhaps as part of a matrix repair or remodelling process.
A Study of Changes in Morphology of Osteoarthritic Articular Cartilage Using Computerized Image Analysis  [PDF]
Neeru Goyal,Madhur Gupta
Journal of Histology , 2013, DOI: 10.1155/2013/981305
Abstract: Histological studies on articular cartilage have been traditionally based on individual observations but this approach is limited by its subjectivity and bias, yielding considerable variability. So the present study was conducted to observe the various changes in the morphology of osteoarthritic femoral articular cartilage using computerized image analysis. The cartilage specimens were divided into two groups: group 1 ( ) (46–81 years) consisted of OA specimens. Group 2 ( ) (41–86 years) consisted of non-OA specimens. A 5?μm thick paraffin sections were stained with H&E staining and analyzed using Image-Pro Express image analysis software for quantitative analysis of articular cartilage. Various parameters, namely, total thickness of the cartilage, area of lacunae in each zone, area of subchondral cavities, and number of chondrocytes per 10,000?μm2 area in each zone, were measured. Microscopic appearance of OA cartilage was much different as compared to control. Various changes seen were different in all specimens and they were not related to age. Lacunar size in all four zones was found to differ significantly in the OA (group 1) and control (group 2) ( ). The results suggest that OA should be considered as a specific process and not simply as an inevitable feature of ageing. 1. Introduction Articular cartilage undergoes substantial structural and molecular changes with age, including surface fibrillation, alteration of structure and composition of collagen, and decrease in strength. Such changes increase the risk of synovial joint degeneration that leads to osteoarthritis (OA), which is a degenerative joint disease characterized by articular cartilage degeneration. It is the most common of the various articular disorders affecting man. Loss of articular cartilage is the major cause of joint dysfunction and disability in OA. Since its early development, digital microscopic image analysis has offered the potential for improving the objectivity of microscopic observations. Substantial efforts have already been made to convert the evaluations of experienced pathologists into quantitative values in various research and diagnostic fields [1–3]. In a previous study, using computerized image analysis we observed the changes in the morphology of the non-OA femoral articular cartilage with age and only the lacunar size in zone 3 was found to correlate significantly with age. Despite this difference in lacunar size, normal histology, that is, four zones could be identified in all non-OA specimens though minor changes in the superficial zone, was observed in the
Postnatal development of collagen structure in ovine articular cartilage
Mark C van Turnhout, Henk Schipper, Bas Engel, Willem Buist, Sander Kranenbarg, Johan L van Leeuwen
BMC Developmental Biology , 2010, DOI: 10.1186/1471-213x-10-62
Abstract: Predominant collagen orientation is parallel to the articular surface throughout the tissue depth for perinatal cartilage. This remodels to the Benninghoff structure before the sheep reach sexual maturity. Remodelling of predominant collagen orientation starts at a depth just below the future transitional zone. Tissue retardance shows a minimum near the articular surface at all ages, which indicates the presence of zonal differentiation at all ages. The absolute position of this minimum does change between birth and maturity. Between different anatomical sites, we find differences in the dynamics of collagen remodelling, but no differences in adult collagen structure.The collagen network in articular cartilage remodels between birth and sexual maturity from a network with predominant orientation parallel to the articular surface to a Benninghoff network. The retardance minimum near, but not at, the articular surface at all ages shows that a zonal differentiation is already present in the perinatal animals. In these animals, the zonal differentiation can not be correlated to the collagen network orientation. We find no difference in adult collagen structure in the nearly congruent metacarpophalangeal joint, but we do find differences in the dynamics of collagen network remodelling.The articulating ends of bones in the diarthrodial joints are covered with a thin layer of articular cartilage (AC). During early development AC functions as a surface growth plate for the underlying bone [1-3]. In adult life, AC functions as a load bearing surface that transmits loads and provides a low friction environment. Between birth and skeletal maturity, AC has to accommodate both developmental and load bearing demands.AC has been shown to develop from a fairly homogeneous tissue to a tissue with site specific composition [1,4,5] and site specific mechanical properties [6]. It is accepted that this development is affected by mechanical loads [7-9] that vary over the joint surfaces [
Relationship between triphasic mechanical properties of articular cartilage and osteoarthritic grade
HaiJun Niu,ChengRui Liu,Ang Li,Qing Wang,YueXiang Wang,DeYu Li,YuBo Fan
Science China Life Sciences , 2012, DOI: 10.1007/s11427-012-4326-7
Abstract: The purpose of this study was to explore the triphasic mechanical properties of osteoarthritic cartilage with different pathological grades. First, samples of cartilage from rabbits with different stages of osteoarthritis (OA) were graded. Following this, the cartilage was strained by a swelling experiment, and changes were measured using a high-frequency ultrasound system. The result, together with fixed charge density and water volume fraction of cartilage samples, was used to estimate the uniaxial modulus of the cartilage tissue, based on a triphasic model. For the control cartilage samples, the uniaxial elastic modulus on the cartilage surface was lower than those in the middle and deep layers. With an increase in the OA grade, the uniaxial elastic modulus of the surface, middle and deep layers decreased. A significant difference was found in the surface elastic modulus of different OA grades (P<0.01), while no significant differences were identified for OA cartilages of Grades 1 and 2 in the middle and deep layers (P<0.01). Compared with Grades 1 and 2, there was a significant reduction in the elastic modulus in the middle and deep layers of Grade 3 OA cartilage (P<0.05). Overall, this study may provide a new quantitative method to evaluate the severity of OA using the mechanical properties of cartilage tissue.
Postnatal development of depth-dependent collagen density in ovine articular cartilage
Mark C van Turnhout, Henk Schipper, Barend van Lagen, Han Zuilhof, Sander Kranenbarg, Johan L van Leeuwen
BMC Developmental Biology , 2010, DOI: 10.1186/1471-213x-10-108
Abstract: Collagen density increases from birth to maturity up to our last sample point (72 weeks). Collagen density increases at the articular surface from 0.23 g/ml ± 0.06 g/ml (mean ± s.d., n = 48) at 0 weeks to 0.51 g/ml ± 0.10 g/ml (n = 46) at 72 weeks. Maximum collagen density in the deeper cartilage increases from 0.39 g/ml ± 0.08 g/ml (n = 48) at 0 weeks to 0.91 g/ml ± 0.13 g/ml (n = 46) at 72 weeks. Most collagen density profiles at 0 weeks (85%) show a valley, indicating a minimum, in collagen density near the articular surface. At 72 weeks, only 17% of the collagen density profiles show a valley in collagen density near the articular surface. The fraction of profiles with this valley stabilises at 36 weeks.Collagen density in articular cartilage increases in postnatal life with depth-dependent variation, and does not stabilize up to 72 weeks, the last sample point in our study. We find strong evidence for a valley in collagen densities near the articular surface that is present in the youngest animals, but that has disappeared in the oldest animals. We discuss that the retardance valley (as seen with polarised light microscopy) in perinatal animals reflects a decrease in collagen density, as well as a decrease in collagen fibril anisotropy.Articular cartilage (AC) is the thin layer of soft tissue that covers the articulating ends of the bones in diarthrodial joints. Healthy adult AC is characterised by a depth-dependent composition [1-3] and structure [4-7]. These characteristics result in depth-dependent mechanical properties [8-11] that are important for the functions of adult AC, specifically load distribution and the establishment of a low friction environment [11-13].AC consists of a number of cells (chondrocytes, ≈ 2% to 5% of the wet volume, [14]) embedded in a porous extracellular matrix (ECM) that is saturated with fluid (≈ 80% wet weight). The ECM consists of collagen and negatively charged proteoglycan molecules. Collagen is the most abundant ECM compone
Adeno-Associated Vector mediated gene transfer of Transforming Growth Factor-beta1 to normal and osteoarthritic human chondrocytes stimulates cartilage anabolism  [cached]
Ulrich-Vinther M.,Stengaard C.,Schwarz E. M.,Goldring M. B.
European Cells and Materials (ECM) , 2005,
Abstract: The objective of the present study was to investigate whether cartilage anabolism in human primary osteoarthritic chondrocytes could be improved by adeno-associated virus (AAV) vector-mediated gene transduction of transforming growth factor TGF-beta1 (TGF-beta1). A bi-cistronic AAV-TGF-beta1-IRES-eGFP (AAV-TGF-beta1) vector was generated and used for transduction of a normal human articular chondrocyte cell line (tsT/AC62) and primary human osteoarthritic articular chondrocytes harvested from 8 patients receiving total knee joint arthroplasty. Transduction efficiency was detected by fluorescent microscopy for gene expression of enhanced green fluorescent protein (eGFP). TGF-beta1 synthesis was determined by ELISA. To assess the influence of TGF-beta1 gene therapy on chondrocyte cartilage metabolism, mRNA expressions of type II collagen, aggrecan, and matrix metalloproteinase 3 (MMP-3) were determined by quantitative real-time PCR. AAV-TGF-beta1 transduction resulted in increased synthesis of TGF-beta1 in both osteoarthritic chondrocytes and the normal articular chondrocyte cell line. The expression levels of the transduced genes were correlated to "multiplicity of infection" (MOI) and post-infectious time. In both osteoarthritic chondrocytes and the normal articular chondrocyte cell line, AAV-TGF-beta1 treatment increased mRNA expression of both type II collagen and aggrecan, but decreased MMP-3 mRNA expression. Osteoarthritic chondrocytes and the normal articular chondrocyte cell line could be transduced with equal efficiencies. In conclusion, it was demonstrated that AAV-TGF-beta1 gene transfer stimulates cartilage anabolism and decreases expression of enzymes responsible for cartilage degradation in human osteoarthritic chondrocytes. The results indicate that the AAV vector is an efficient mediator of growth factors to human articular chondrocytes, and that it might be useful in future chondrocyte gene therapy.
Reference genes for normalization of gene expression studies in human osteoarthritic articular cartilage
Manuel Pombo-Suarez, Manuel Calaza, Juan J Gomez-Reino, Antonio Gonzalez
BMC Molecular Biology , 2008, DOI: 10.1186/1471-2199-9-17
Abstract: Analyses of expression stability in cartilage from 10 patients with hip OA, 8 patients with knee OA and 10 controls without OA were done with classical statistical tests and the software programs geNorm and NormFinder. Results from the three methods of analysis were broadly concordant. Some of the commonly used reference genes, GAPDH, ACTB and 18S RNA, performed poorly in our analysis. In contrast, the rarely used TBP, RPL13A and B2M genes were the best. It was necessary to use together several of these three genes to obtain the best results. The specific combination depended, to some extent, on the type of samples being compared.Our results provide a satisfactory set of previously unused reference genes for qPCR in hip and knee OA This confirms the need to evaluate the suitability of reference genes in every tissue and experimental situation before starting the quantitative assessment of gene expression by qPCR.Osteoarthritis (OA) is the most common rheumatic disease and a leading cause of disability in the elderly [1]. It involves ligaments, subchondral bone, synovium and cartilage [2,3]. Most research in OA has been focused in articular cartilage where the disease becomes highly evident in its late stages. Biochemical changes in chondrocytes and extracellular matrix components are followed by macroscopic lesions including thinning, fibrillation, fissuring and erosion of cartilage that will eventually lead to denudation of subchondral bone. These changes result from active processes that involve matrix destruction and inefficient repair [4-6]. Progress in the management of OA requires better knowledge of the regulation of these processes as they could have a different impact depending on its etiology. The commonest form of OA is idiopathic and appears only in the elderly. Nevertheless, some forms of OA have a genetic cause or are secondary to rheumatic, endocrine, metabolic or neuropathic diseases or to local factors like trauma, infection or avascular necrosis [7
Cartilage collagen damage in hip osteoarthritis similar to that seen in knee osteoarthritis; a case–control study of relationship between collagen, glycosaminoglycan and cartilage swelling
Hosseininia Shahrzad,Lindberg Lisbeth R,Dahlberg Leif E
BMC Musculoskeletal Disorders , 2013, DOI: 10.1186/1471-2474-14-18
Abstract: Background It remains to be shown whether OA shares molecular similarities between different joints in humans. This study provides evidence for similarities in cartilage molecular damage in osteoarthritic (OA) joints. Methods Articular cartilage from osteoarthritic hip joints were analysed and compared to non-OA controls regarding collagen, glycosaminoglycan and water content. Femoral heads from 16 osteoarthritic (OA) and 20 reference patients were obtained from hip replacement surgery due to OA and femoral neck fracture, respectively. Cartilage histological changes were assessed by Mankin grading and denatured collagen type II immunostaining and cartilage was extracted by α-chymotrypsin. Hydroxyproline and Alcian blue binding assays were used to measure collagen and glycosaminoglycan (GAG) content, respectively. Results Mankin and immunohistology scores were significantly higher in hip OA samples than in reference samples. Cartilage water content was 6% higher in OA samples than in references. 2.5 times more collagen was extracted from OA than from reference samples. There was a positive association between water content and percentage of extractable collagen pool (ECP) in both groups. The amounts of collagen per wet and dry weights did not differ statistically between OA and reference cartilage. % Extractable collagen was not related to collagen per dry weight in either group. However when collagen was expressed by wet weight there was a negative correlation between % extractable and collagen in OA cartilage. The amount of GAG per wet weight was similar in both groups but the amount of GAG per dry weight was higher in OA samples compared to reference samples, which suggests a capacity for GAG biosynthesis in hip OA cartilage. Neither of the studied parameters was related to age in either group. Conclusions Increased collagen extractability and water content in human hip cartilage is associated with OA pathology and can be observed at early stages of the degenerative hip OA process. Our results suggest a common degradative pathway of collagen in articular cartilage of different joints. Furthermore, the study suggests that biochemical changes precede more overt OA changes and that chondrocytes may have a capability to compensate molecular loss in the early phase of OA.
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