Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: A parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry

Keyszer, Gernot; Redlich, A.; Häupl, Thomas; Zacher, J.; Sparmann, M.; Ungethüm, Ute; Burmester, Gerd R.

doi:10.1002/1529-0131(199808)41:8<1378::aid-art6>3.0.co;2-j

Cited by 82 publications

(57 citation statements)

References 38 publications

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“…Destruction of the extracellular matrix is the result of a shifted balance between the matrix degrading enzyme and its inhibitor in favor of the enzyme (14,15). Therefore, we included the investigation of the relationship of cathepsin B and its major inhibitor cystatin C (26) in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Microscopic evaluation of the slides was made according to a modified method of Keyszer et al (14). The immunohistochemical analysis of all slides was performed on the same day.…”

Section: Light Microscopymentioning

confidence: 99%

“…A variety of matrix-degrading enzymes has been suggested to contribute to bone and cartilage damage in other synovial lesions, such as rheumatoid arthritis and pigmented villonodular synovitis. Besides matrix metalloproteinases (MMP), the cysteine proteinases cathepsin B and the recently found Type K are especially involved in the destruction of the extracellular matrix (13)(14)(15)(16)(17). Cathepsin B is able to degrade different types of collagen and proteoglycans as well as the bone matrix protein osteocalcin (16,17).…”

mentioning

confidence: 99%

“…Because matrix destruction may be a result of a shifted equilibrium between the proteinase and its inhibitor (14,15), we examined the expression of both cathepsin B and its most potent endogenous inhibitor, cystatin C (26). Immunohistochemical techniques, including doublelabeling methods, were performed to analyze the colocalization of cathepsin B and cystatin C. Furthermore, cells expressing the respective molecules were determined by double staining with the macrophage markers HAM56 (in the case of cathepsin B) or anti-CD68 (in the case of cystatin C).…”

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confidence: 99%

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Expression of Cysteine Proteinases Cathepsins B and K and of Cysteine Proteinase Inhibitor Cystatin C in Giant Cell Tumor of Tendon Sheath

Hansen

Gäumann

et al. 2001

Modern Pathology

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The expression of cysteine proteinases cathepsins B and K and of the endogenous inhibitor of cysteine proteinases, cystatin C, was investigated in tissue specimens of patients with giant cell tumor of tendon sheath (GCTTS). Expression of both enzymes was examined by immunohistochemistry in tissue specimens of 14 patients with GCTTS. Applying double-labeling techniques, the coexpression of cathepsin B and its major endogenous inhibitor cystatin C was additionally studied. Cells expressing the respective proteins were further characterized with the macrophage markers HAM56 and anti-CD68 (clone PG-M1). Cathepsin B could be detected in numerous HAM56-positive mononuclear cells (MC), but only in very few giant cells (GC). In contrast, cathepsin K was predominantly identified in GC that were also strongly immunoreactive for cystatin C and CD68. Coexpression of cathepsin B and cystatin C occurred only in a few MC. The strong expression of both cathepsin B and K suggests that in GCTTS, bone erosion might be mediated not only by pressure of the proliferative tissue, but also by matrix-degrading cysteine proteinases. Because previous studies showed that osteoclasts express high levels of CD68, cathepsin K, and cystatin C but not of cathepsin B, our study contributes to the view that GC of GCTTS and osteoclasts are closely associated.

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Section: Discussionmentioning

confidence: 99%

“…Microscopic evaluation of the slides was made according to a modified method of Keyszer et al (14). The immunohistochemical analysis of all slides was performed on the same day.…”

Section: Light Microscopymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Expression of Cysteine Proteinases Cathepsins B and K and of Cysteine Proteinase Inhibitor Cystatin C in Giant Cell Tumor of Tendon Sheath

Hansen

Gäumann

et al. 2001

Modern Pathology

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“…3 Synovial fibroblasts (SF) have been shown to exhibit features of cellular activation 4 reflected by the enhanced expression of proto-oncogenes such as c-ras, c-myc, c-fos. Moreover, in RA-SF alterations in tumorsuppressor genes 5 and enhanced production of effector molecules, that is, proinflammatory cytokines, adhesion molecules 6 and matrix degrading enzymes such as matrix metalloproteinases, 7 members of the plasminogen-plasmin system 8 and cathepsins 9 have been reported. By expression and secretion of matrix-degrading enzymes, SF have been demonstrated to invade and degrade cartilage and bone; 10 however, the functional relevance of cathepsin L (CL) has not been proven so far.…”

Section: Introductionmentioning

confidence: 99%

Targeting cathepsin L (CL) by specific ribozymes decreases CL protein synthesis and cartilage destruction in rheumatoid arthritis

et al. 2004

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The present study was undertaken to examine whether ribozymes cleaving specifically cathepsin L (CL) mRNA are able to decrease the synthesis of CL protease in rheumatoid arthritis synovial fibroblasts (RA-SF) and thereby reduce the invasiveness into cartilage both in vitro and in the SCID mouse coimplantation model of RA. Two different ribozymes that cleave CL mRNA specifically at positions 533 (RzCL533) and 790 (RzCL790) were generated. Using retroviral gene transfer, RA-SF were transduced with the ribozyme constructs or the empty vector. To examine the effect of the ribozymes on the mRNA level, quantitative analysis for CL mRNA was performed using real-time PCR. For evaluation on the protein level, ELISA using specific anti-CL antibodies was performed. In addition, transduced RA-SF were examined in vitro in a three-dimensional destruction assay evaluating their ability to degrade extracellular matrix produced by human chondrocytes. Matrix destruction was monitored by the release of soluble glycosaminoglycans (sGAG). Using the in vivo SCID mouse coimplantation model of RA, RzCL533-transduced RA-SF and control cells were coimplanted with human cartilage for 60 days. After being killed, invasion of RA-SF into the cartilage was evaluated by using a semiquantitative score. Transduction of RA-SF with RzCL533 and RzCL790 ribozymes decreased significantly the expression of CL mRNA to 44% (range 25-62%) and 20% (range 1-43%), respectively, when compared to mocktransduced cells. The protein concentration of CL in the cell culture supernatants of transduced RA-SF was decreased from 16.0 ng/ml in the mock constructs to 4.1 and 8.2 ng/ml (mean), respectively. Using the in vitro cartilage destruction assay, the release of sGAG decreased to 46 and 60%, respectively, after 14 days when compared to mocktransduced cells. In the SCID mouse coimplantation model of RA, RzCL533-transduced RA-SF revealed a significant lower cartilage invasion when compared to mock and untransduced cells. Using retroviral gene transfer, ribozymes cleaving CL mRNA inhibit specifically the synthesis of this matrix-degrading enzyme and reduce cartilage destruction in in vitro and in vivo models. Our study therefore suggests that ribozymes targeting CL could be a novel and efficient tool to inhibit joint destruction in RA.

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Increased expression of extracellular matrix metalloproteinase inducer in rheumatoid synovium

Konttinen

Mandelin

et al. 2000

Arthritis & Rheumatism

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Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: A parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry

Cited by 82 publications

References 38 publications

Expression of Cysteine Proteinases Cathepsins B and K and of Cysteine Proteinase Inhibitor Cystatin C in Giant Cell Tumor of Tendon Sheath

Expression of Cysteine Proteinases Cathepsins B and K and of Cysteine Proteinase Inhibitor Cystatin C in Giant Cell Tumor of Tendon Sheath

Targeting cathepsin L (CL) by specific ribozymes decreases CL protein synthesis and cartilage destruction in rheumatoid arthritis

Increased expression of extracellular matrix metalloproteinase inducer in rheumatoid synovium

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