Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis

Boris V. Shlopov, Marina L. Gumanovskaya, Karen Hasty

Research output: Contribution to journalArticle

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Abstract

Objective. To correlate the increased collagenase production previously seen in chondrocytes isolated from osteoarthritic (OA) lesions and the expression of cytokines and cytokine receptors. Methods. Chondrocytes were isolated from OA cartilage and characterized for synthesis of collagenases, cytokines, and cytokine receptors by Northern and Western blot analyses, RNA protection assay, and flow cytometry. Results. Chondrocytes located in cartilage proximal to the macroscopic OA lesions bound more tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) compared with chondrocytes isolated from morphologically normal cartilage from the same joint. In response to TNFα stimulation, messenger RNA (mRNA) levels for the IL-1 receptor I (IL-1RI), IL-1RII, TNF receptor II (TNFR II), and IL-6 receptor as well as the level of proinflammatory cytokines, such as IL-1α, IL-1β, lymphotoxin β, TNFα, and IL-6, also increased. In contrast, treatment with transforming growth factor β1 (TGFβ1) resulted in down-regulation of matrix metalloproteinase 1 (MMP-1) and MMP-13 concomitant with a reduction in the levels of mRNA for IL-1RI, IL-1RII, TNFRI, and TNFRII and proinflammatory cytokine levels. In contrast, the levels of mRNA for TGFβ receptor I, TGFβ1, and TGFβ3 were up-regulated. Conclusion. These data show that TGFβ1 has antagonistic effects upon OA chondrocytes, in contrast to the effects seen with TNFα. The cyclical course of OA, where a period of active disease is followed by a period of remission, can be explained by a sequential pattern of cytokine stimulation followed by a feedback inhibition of autocrine cytokine production and cytokine receptor expression, thus affecting collagenase synthesis.

Original languageEnglish (US)
Pages (from-to)195-205
Number of pages11
JournalArthritis and Rheumatism
Volume43
Issue number1
DOIs
StatePublished - Jan 1 2000

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Matrix Metalloproteinase 13
Osteoarthritis
Chondrocytes
Cytokines
Cytokine Receptors
Transforming Growth Factors
Collagenases
Tumor Necrosis Factor-alpha
Interleukin-1
Cartilage
Interleukin-1 Receptors
Messenger RNA
Interleukin-6 Receptors
Lymphotoxin-alpha
Matrix Metalloproteinase 1
Tumor Necrosis Factor Receptors
Matrix Metalloproteinases
Northern Blotting
Interleukin-6
Flow Cytometry

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. / Shlopov, Boris V.; Gumanovskaya, Marina L.; Hasty, Karen.

In: Arthritis and Rheumatism, Vol. 43, No. 1, 01.01.2000, p. 195-205.

Research output: Contribution to journalArticle

Shlopov, Boris V. ; Gumanovskaya, Marina L. ; Hasty, Karen. / Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. In: Arthritis and Rheumatism. 2000 ; Vol. 43, No. 1. pp. 195-205.
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AB - Objective. To correlate the increased collagenase production previously seen in chondrocytes isolated from osteoarthritic (OA) lesions and the expression of cytokines and cytokine receptors. Methods. Chondrocytes were isolated from OA cartilage and characterized for synthesis of collagenases, cytokines, and cytokine receptors by Northern and Western blot analyses, RNA protection assay, and flow cytometry. Results. Chondrocytes located in cartilage proximal to the macroscopic OA lesions bound more tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) compared with chondrocytes isolated from morphologically normal cartilage from the same joint. In response to TNFα stimulation, messenger RNA (mRNA) levels for the IL-1 receptor I (IL-1RI), IL-1RII, TNF receptor II (TNFR II), and IL-6 receptor as well as the level of proinflammatory cytokines, such as IL-1α, IL-1β, lymphotoxin β, TNFα, and IL-6, also increased. In contrast, treatment with transforming growth factor β1 (TGFβ1) resulted in down-regulation of matrix metalloproteinase 1 (MMP-1) and MMP-13 concomitant with a reduction in the levels of mRNA for IL-1RI, IL-1RII, TNFRI, and TNFRII and proinflammatory cytokine levels. In contrast, the levels of mRNA for TGFβ receptor I, TGFβ1, and TGFβ3 were up-regulated. Conclusion. These data show that TGFβ1 has antagonistic effects upon OA chondrocytes, in contrast to the effects seen with TNFα. The cyclical course of OA, where a period of active disease is followed by a period of remission, can be explained by a sequential pattern of cytokine stimulation followed by a feedback inhibition of autocrine cytokine production and cytokine receptor expression, thus affecting collagenase synthesis.

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