Collagen synthesis in normal and osteoarthritic human cartilage.

Lippiello, Louis; Hall, D.; Mankin, Henry J.

doi:10.1172/jci108676

Cited by 230 publications

(118 citation statements)

References 29 publications

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“…Our observation that type II collagen synthesis and processing were increased in osteoarthritic cartilage is consistent with microarray data (7), in situ hybridization studies (21), and early work using [ 3 H]proline incorporation (22). In contrast, Kumar et al (23), who sequenced cDNA libraries derived from OA and normal cartilage, did not observe differences in type II collagen mRNA expression.…”

Section: Discussionsupporting

confidence: 91%

Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin βA (Activin A), a Regulatory Molecule for Chondrocytes

Hermansson

Sawaji

Bolton

et al. 2004

Journal of Biological Chemistry

156

141

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We show that proteomic analysis can be applied to study cartilage pathophysiology. Proteins secreted by articular cartilage were analyzed by two-dimensional SDS-PAGE and mass spectrometry. Cartilage explants were cultured in medium containing [ 35 S]methionine/cysteine to radiolabel newly synthesized proteins. To resolve the cartilage proteins by two-dimensional electrophoresis, it was necessary to remove the proteoglycan aggrecan by precipitation with cetylpyridinium chloride. 50 -100 radiolabeled protein spots were detected on two-dimensional gels of human cartilage cultures. Of 170 silverstained proteins identified, 19 were radiolabeled, representing newly synthesized gene products. Most of these were known cartilage constituents. Several nonradiolabeled cartilage proteins were also detected. The secreted protein pattern of explants from 12 osteoarthritic joints (knee, hip, and shoulder) and 14 nonosteoarthritic adult joints were compared. The synthesis of type II collagen was strongly up-regulated in osteoarthritic cartilage. Normal adult cartilage synthesized little or no type II collagen in contrast to infant and juvenile cartilage. Potential regulatory molecules novel to cartilage were identified; pro-inhibin ␤A and processed inhibin ␤A (which dimerizes to activin A) were produced by all the osteoarthritic samples and half of the normals. Connective tissue growth factor and cytokine-like protein C17 (previously only identified as an mRNA) were also found. Activin induced the tissue inhibitor for metalloproteinases-1 in human chondrocytes. Its expression was induced in isolated chondrocytes by growth factors or interleukin-1. We conclude that type II collagen synthesis in articular cartilage is down-regulated at skeletal maturity and reactivated in osteoarthritis in attempted repair and that activin A may be an anabolic factor in cartilage. Osteoarthritis (OA)1 is a common joint disease characterized by degeneration of articular cartilage. Since cartilage has very limited capacity for repair, the loss is effectively irreversible. Prevalence studies show that most people over the age of 65 have some evidence of the disease (1, 2). Little is known about the molecular mechanism of cartilage destruction in OA, particularly the early events. It is thought that there is an imbalance between anabolism and catabolism of the extracellular matrix, there being an increase in catabolism. It has been suggested that this increased breakdown of matrix is due to the production of degradative enzymes such as the matrix metalloproteinases (MMPs) and members of the disintegrin and metalloproteinase (ADAM) family (3, 4). The increase in proteinase expression may be due to inflammatory cytokines such as interleukin-1 (Il-1) and tumor necrosis factor (4, 5). However, it is unclear whether these degradative processes are a primary event or a secondary reaction.Articular cartilage consists mainly of extracellular matrix, the principal organic components of which are type II collagen fibers and aggregates of the large proteoglycan...

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Section: Discussionsupporting

confidence: 91%

Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin βA (Activin A), a Regulatory Molecule for Chondrocytes

Hermansson

Sawaji

Bolton

et al. 2004

Journal of Biological Chemistry

156

141

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“…[7][8][9] This activity of OA chondrocytes is generally appreciated as an attempt to restore the ECM. In different studies with biochemical and molecular biology approaches, type II collagen synthesis was found to be increased between four-and sevenfold during OA.…”

mentioning

confidence: 99%

Regulation of Type II Collagen Synthesis during Osteoarthritis by Prolyl-4-Hydroxylases

Grimmer

Balbus

Lang

et al. 2006

The American Journal of Pathology

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Osteoarthritic (OA) chondrocytes are metabolically active, displaying increased synthesis of type II collagen. Here, we show by immunohistochemistry and polymerase chain reaction that in comparison with healthy cartilage, OA articular chondrocytes exhibit increased in vivo synthesis of collagen prolyl-4-hydroxylase type II, a pivotal enzyme in collagen triple helix formation. Exposure of primary human articular chondrocytes to 1% oxygen enhanced accumulation of native type II collagen and stabilized hypoxia-inducible factor-1␣ (HIF-1␣). This effect was abolished by addition of the HIF-1 inhibitor 2-methoxyestradiol. Real-time polymerase chain reaction analyses of mRNAs from these cultures revealed increased transcript levels of both ␣-subunits of prolyl-4-hydroxylase (P4HA1, ϳ2-fold; P4HA2, ϳ2.3-fold) and of classical HIF-1 target genes (glucosetransporter-1, ϳ2.1-fold; phosphoglyceratekinase-1, ϳ2.2-fold). Treatment of hypoxic chondrocytes with 2-methoxyestradiol reduced transcriptional activity of HIF-1 and synthesis of ␣(II), and to a lesser extent ␣(I), subunits of collagen prolyl-4-hydroxylases. mRNA levels of type II collagen (Col2A1) and the ␤-subunit (P4HB) of prolyl-4-hydroxylase, however, displayed only modest changes at 1% oxygen. From these results and our in vivo data, we inferred that besides increased Articular hyaline cartilage is the most important component in synovial joints for frictionless joint motion. During movement, the articular cartilage is compressed by load and is then able to recover from this deformity. These unique biomechanical properties depend on the specific zonal architecture of articular cartilage as well as the extracellular matrix (ECM), which consists of two phases: solid and fluid phases. The main ECM components are proteoglycans, glycoproteins, and collagens, mainly type II collagen.1-3 Type II collagen is synthesized as a procollagen molecule with noncollagenous amino and carboxy extension peptides, by articular chondrocytes which represent the only living elements within hyaline cartilage. 4 Large type II collagen fibrils form a network with embedded proteoglycans, glycoproteins, water, and soluble ions. Since this collagen network is established in adults, the half-life of collagens is estimated to be over decades.Proper function of a load-bearing joint depends on the structural integrity of this highly specialized cartilage tissue and its ability to absorb and respond to mechanical stress. During the course of osteoarthritis, increased degradation processes of the ECM by mechanical factors as well as activity of metalloproteinases and aggrecanases have been observed. 5,6 Ultimately, destruction of large parts of the collagen network and ion-binding capacity via loss of negatively charged proteoglycans lead to a significantly decreased water-binding capability of the ECM. These biochemical changes are responsible for the devel-

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“…The chondro-cyte response may lead, in certain situations, to longterm changes in the phenotype of the cell, and therefore to an inability to properly repair or maintain the cartilage ECM (4). This is exemplified by the phenotypic changes in the patterns of production or in the temporal or spatial distribution of the synthesis of interstitial collagens, fibroblast-type proteoglycans, and production of ECM proteins associated with fetal development that occur during the development of osteoarthritis (OA), dedifferentiation in culture, or in response to certain types of cartilage injury (6)(7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Assessment of the gene expression profile of differentiated and dedifferentiated human fetal chondrocytes by microarray analysis

Stokes¹,

Liu²,

Coimbra³

et al. 2002

Arthritis & Rheumatism

152

106

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Objective. To study the changes in patterns of gene expression exhibited by human chondrocytes as they dedifferentiate into fibroblastic cells in culture in order to better understand the mechanisms that control this process and its relationship to the phenotypic changes that occur in chondrocytes during the development of osteoarthritis (OA).Methods. Human fetal epiphyseal chondrocytes (HFCs) were cultured either on poly-(2-hydroxyethyl methacrylate)-coated plates (differentiated HFC cultures) or in plastic tissue culture flasks as monolayers (dedifferentiated HFC cultures). Following 11 days of culture under either condition, poly(A؉) RNA was isolated from the two cell populations and subjected to a gene expression analysis using a microarray containing ϳ5,000 known human genes and ϳ3,000 expressed sequence tags (ESTs).Results. A >2-fold difference in the expression of 62 known genes and 6 ESTs was observed between the two cell types. The differences in expression of several of the genes detected by the microarray hybridization were confirmed by Northern analyses. Two transcription factor genes, TWIST and HIF-1␣, and a cellular adhesion protein gene, cadherin 11, were markedly regulated in response to differentiation and dedifferentiation. Expression of these genes was also detected in adult normal and OA cartilage and chondrocytes. Analysis of the gene expression profile of HFCs revealed a complex pattern of gene expression, including many genes not yet reported to be expressed by chondrocytes.Conclusion. Chondrocytes in monolayer become dedifferentiated, acquiring a fibroblast-like appearance and changing their pattern of gene expression from one of expression of chondrocyte-specific genes to one that resembles a fibroblastic or chondroprogenitor-like pattern. Changes in gene expression associated with the process of dedifferentiation of HFCs in vitro were observed in a wide variety of genes, including genes encoding extracellular matrix proteins, transcription factors, and growth factors. At least 3 of the genes that were regulated in response to dedifferentiation were also found to be expressed in adult normal and OA articular cartilage and chondrocytes.

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Collagen synthesis in normal and osteoarthritic human cartilage.

Cited by 230 publications

References 29 publications

Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin βA (Activin A), a Regulatory Molecule for Chondrocytes

Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin βA (Activin A), a Regulatory Molecule for Chondrocytes

Regulation of Type II Collagen Synthesis during Osteoarthritis by Prolyl-4-Hydroxylases

Assessment of the gene expression profile of differentiated and dedifferentiated human fetal chondrocytes by microarray analysis

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