Activation of collagen type II expression in osteoarthritic and rheumatoid cartilage

Aigner, Thomas; Stöß, H; Weseloh, G.; Zeiler, Gareth Edward; Mark, Klaus von der

doi:10.1007/bf02899701

Cited by 137 publications

(99 citation statements)

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“…It is well known that in OA, at least a portion of the remaining functional chondrocytes is highly metabolically active (49). This metabolic activity can be interpreted as a compensatory anabolic response counteracting increased catabolism (50).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Grimmer¹,

Pfander²,

Swoboda³

et al. 2007

Arthritis & Rheumatism

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Objective. To investigate crosslinks between catabolic and anabolic pathways in articular cartilage by examining the synthesis and distribution pattern of microsomal prostaglandin E synthase 1 (mPGES-1) in healthy and osteoarthritic (OA) cartilage and analyzing its functional relationship to hypoxia-inducible factor 1␣ (HIF-1␣) in primary articular chondrocytes.Methods. Normal cartilage and OA cartilage were subjected to immunohistochemical staining for mPGES-1 and HIF-1␣. Isolated chondrocytes were cultivated under 21% or 1% O 2 . Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction were used to detect genes differentially expressed in chondrocytes cultured under normoxic compared with hypoxic conditions. Immunoblotting was conducted to evaluate intracellular protein levels of mPGES and nuclear accumulation of HIF-1␣ under different oxygen tension levels and with different stimulatory or inhibitory chemical agents.Results. We found enhanced levels of expression of the mPGES-1 gene and an increased number of OA chondrocytes showing staining for mPGES-1 in OA cartilage. Microarray analysis demonstrated that mPGES-1 was among the genes that were up-regulated to the greatest degree in primary chondrocytes exposed to 1% O 2 . In vitro, hypoxia led to an enhanced synthesis of mPGES-1, coinciding with a nuclear accumulation of the transcription factor HIF-1␣. In chondrocyte culture, stimulation with dimethyloxaloylglycine promoted the expression of mPGES-1, phosphoglycerate kinase 1, and cyclooxygenase 2 (COX-2) by stabilizing HIF-1␣ protein levels. A reduction of mPGES-1 synthesis was detected after treatment with 2-methoxyestradiol, correlating with lower HIF-1␣ activity. In contrast, synthesis of mPGES-1 was not influenced by treatment with the specific COX-2 inhibitor NS398.Conclusion. These findings suggest that the transcription factor HIF-1␣ is involved in the up-regulation of mPGES-1 and may therefore play an important role in the metabolism of OA cartilage.The regulation of the metabolism of articular cartilage involves a complex network of a multitude of signaling pathways. In osteoarthritis (OA), the usually well-regulated maintenance between extracellular matrix synthesis and degradation is greatly disturbed. Inflammatory cytokines promote catabolism by inducing expression of matrix-degrading enzymes, which lead to the breakdown of the collagen network and the release of cartilage proteoglycans (1). The biologic effects of interleukin-1␤ (IL-1␤), one of the key agents in the pathophysiology of OA, are mediated by signaling pathways involving NF-B, JNK, p38, or ERK, by nitric oxide, and by cytokines as well as by prostaglandins (2). Prostaglandin E 2 (PGE 2 ), the most abundant prostaglandin in the skeletal system (3), induces a number of matrix-degrading enzymes, thus stimulating the cataboSupported by the Interdisciplinary Center of Clinical Research Erlangen (Project C2) and the DFG (PF 383/4-1).

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Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Grimmer¹,

Pfander²,

Swoboda³

et al. 2007

Arthritis & Rheumatism

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“…pRNA 1 contains a 294-bp fragment of mouse 18s ribosomal RNA (rRNA). This probe shows 100% homology to human 18s rRNA (9) and was used as a positive control for preservation of the RNA content in the samples during the technical procedures.…”

Section: Methodsmentioning

confidence: 99%

Suppression of cartilage matrix gene expression in upper zone chondrocytes of osteoarthritic cartilage

Aigner

Vornehm

Zeiler³

et al. 1997

Arthritis & Rheumatism

135

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Objective. To evaluate the anabolic activity of osteoarthritic chondrocytes in situ by investigating the messenger RNA (mRNA) expression of 3 major cartilage components, type I1 collagen, aggrecan, and link protein.Methods. In situ hybridization experiments and histochemical analysis for proteoglycan content were performed on parallel sections of normal and osteoarthritic (OA) cartilage specimens.Results. Most chondrocytes in the deeper zones of OA cartilage showed an increase in mRNA expression, in particular, of type I1 collagen and to a lesser extent, aggrecan, compared with normal specimens. However, chondrocytes of the upper zone were largely negative for aggrecan or type I1 collagen mRNA. The expression of link protein mRNA was low in normal and OA specimens.Conclusion. These observations suggest that suppression of the anabolic activity of chondrocytes in the upper zones contributes to the metabolic imbalance observed in OA cartilage. Stimulation of matrix anabolism in superficial chondrocytes might be a suitable target for therapeutic intervention.The unique biomechanical properties of articular cartilage are provided by its extracellular matrix, and the failure of cartilage in joint disease is a consequence of the progressive destruction of this matrix. The extracelMar matrix of articular cartilage consists of 2 major Supported by the Deutsche Forschungsgemeinschaft (DFG Grant Ai 20/1-1).T. Aigner, MD, S. I. Vornehm, BsC, K. von der Mark, PhD: University of Erlangen-Nurnberg, Erlangen, Germany; G. Zeiler, MD: Orthopedic Hospital Wichernhaus, Rummelsberg, Schwarzenbruck, Germany; J. Dudhia, PhD, M. T. Bayliss, PhD: Kennedy Institute of Rheumatology, London, UK.Address reprint requests to T. Aigner, MD, Institute of Pathology, University of Erlangen-Nurnberg, Krankenhausstrasse 8-10, D-91054 Erlangen, Germany.Submitted for publication June 17, 1996; accepted in revised form September 3, 1996. components: the network of types 11, IX, and XI collagen (l), which provides the tensile strength and stiffness of articular cartilage, and the large aggregating proteoglycan, aggrecan, which is responsible for the osmotic swelling capacity, and thus the elasticity, of the cartilage matrix (2,3). Aggrecan associates with hyaluronic acid, and this interaction is stabilized by link protein (4), which shares homology with the hyaluronan-binding (Gl) domain of aggrecan. Other cartilage proteoglycans such as decorin, biglycan, fibromodulin, and versican may be present in the cartilage matrix in equimolar amounts, but have other important functions, such as control of collagen fibril diameter and binding of growth factors (2,5,6). Similarly, type VI collagen, which is specifically found in the pericellular matrix of articular cartilage, presumably plays a crucial role in the establishment of the microenvironment of the chondrocytes (7).In normal adult articular cartilage, the turnover of collagen fibrils is very low (8-lo), whereas a relatively high turnover rate for aggrecan has been measured (11,12). In osteoarthritic...

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“…23 To obtain optimal staining results for the antibodies, we used various enzymatic pretreatments including hyaluronidase (2 mg/ml in phosphate-buffered saline, pH 5, for 60 minutes at 37°C; Boehringer, Mannheim, Germany); pronase (2 mg/ml in phosphate-buffered saline, pH 7.3, for 60 minutes at 37°C; Sigma, Munich, Germany); chondroitinase avidin-biotin complex (0.25 U/ml in 0.1 mol/L Tris-HCl, pH 8, for 60 minutes at 37°C; Sigma); or bacterial protease XXIV (0.02 mg/ml; phosphate-buffered saline, pH 7.3, for 60 minutes at 37°C; Sigma). The optimal assay conditions as well as the source of the antibodies are shown in Table 1.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

Fan

Söder

Oehler³

et al. 2007

The American Journal of Pathology

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120

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Interleukin (IL)-1 is one of the most important catabolic cytokines in rheumatoid arthritis. In this study, we were interested in whether we could identify IL-1 expression and activity within normal and osteoarthritic cartilage. mRNA expression of IL-1␤ and of one of its major target genes, IL-6, was observed at very low levels in normal cartilage, whereas only a minor up-regulation of these cytokines was noted in osteoarthritic cartilage, suggesting that IL-1 signaling is not a major event in osteoarthritis. However, immunolocalization of central mediators involved in IL-1 signaling pathways [38-kd protein kinases, phospho (P)-38-kd protein kinases, extracellular signal-regulated kinase 1/2, P-extracellular signal-regulated kinase 1/2, c-Jun NH 2 -terminal kinase 1/2, P-c-Jun NH 2 -terminal kinase 1/2, and nuclear factor B] showed that the four IL-1 signaling cascades are functional in normal and osteoarthritic articular chondrocytes. In vivo, we found that IL-1 expression and signaling mechanisms were detectible in the upper zones of normal cartilage, whereas these observations were more pronounced in the upper portions of osteoarthritic cartilage. Given these expression and distribution patterns, our data support two roles for IL-1 in the pathophysiology of articular cartilage. First, chondrocytes in the upper zone of osteoarthritic articular cartilage seem to activate catabolic signaling pathways that may be in response to diffusion of external IL-1 from the synovial fluid. Second, IL-1 seems to be involved in normal cartilage tissue homeostasis as shown by identification of baseline expression patterns and signaling cascade activation.

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Activation of collagen type II expression in osteoarthritic and rheumatoid cartilage

Cited by 137 publications

References 35 publications

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Suppression of cartilage matrix gene expression in upper zone chondrocytes of osteoarthritic cartilage

Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

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