Differential patterns of response to doxycycline and transforming growth factor β1 in the down-regulation of collagenases in osteoarthritic and normal human chondrocytes

Boris V. Shlopov, Gerald N. Smith, Ada A. Cole, Karen Hasty

Research output: Contribution to journalArticle

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Abstract

Objective. To investigate the ability of doxycycline, transforming growth factor β1 (TGFβ1), and phorbol myristate acetate (PMA) to modulate collagenase synthesis in osteoarthritic (OA) chondrocytes. Methods. Levels of fibroblast collagenase (matrix metalloproteinase 1 [MMP-1]), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13) proteins and messenger RNA (mRNA) were measured in chondrocytes isolated from involved and uninvolved areas of OA cartilage and from normal human chondrocytes, after treatment with doxycycline, TGFβ1, and PMA. Results. Chondrocytes isolated from cartilage immediately adjacent to the OA lesion had, on average, 1.8-3.9- fold higher basal levels of MMP mRNA. These cells down-regulated collagenase proteins and mRNA upon incubation with TGFβ1. In contrast, chondrocytes from areas located more distant from the macroscopic lesion increased MMP-13 mRNA, while MMP-1 and MMP-8 decreased after stimulation with TGFβ1. Discoordinate regulation was observed after stimulation with PMA, with an increase in MMP- 1 and MMP-8 but a decrease in MMP-13. Incubation of OA chondrocytes with doxycycline (1-10 μg/ml), at pharmacologically achievable levels, decreased levels of mRNA of all 3 collagenases, but not G3PDH. In addition, doxycycline inhibited the increase in mRNA for these enzymes in normal chondrocytes stimulated with tumor necrosis factor α. Conclusion. These findings suggest that regulation of MMP-1, MMP-8, and MMP-13 in OA chondrocytes, although mediated by differing pathways, can be decreased by treatment with doxycycline at low concentrations. Our data provide a rationale for the use of doxycycline in the treatment of OA.

Original languageEnglish (US)
Pages (from-to)719-727
Number of pages9
JournalArthritis and rheumatism
Volume42
Issue number4
DOIs
StatePublished - Apr 1 1999

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Doxycycline
Transforming Growth Factors
Collagenases
Chondrocytes
Matrix Metalloproteinases
Down-Regulation
Messenger RNA
Matrix Metalloproteinase 1
Tetradecanoylphorbol Acetate
Matrix Metalloproteinase 8
Matrix Metalloproteinase 13
Cartilage
Proteins
Tumor Necrosis Factor-alpha

All Science Journal Classification (ASJC) codes

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

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Differential patterns of response to doxycycline and transforming growth factor β1 in the down-regulation of collagenases in osteoarthritic and normal human chondrocytes. / Shlopov, Boris V.; Smith, Gerald N.; Cole, Ada A.; Hasty, Karen.

In: Arthritis and rheumatism, Vol. 42, No. 4, 01.04.1999, p. 719-727.

Research output: Contribution to journalArticle

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AB - Objective. To investigate the ability of doxycycline, transforming growth factor β1 (TGFβ1), and phorbol myristate acetate (PMA) to modulate collagenase synthesis in osteoarthritic (OA) chondrocytes. Methods. Levels of fibroblast collagenase (matrix metalloproteinase 1 [MMP-1]), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13) proteins and messenger RNA (mRNA) were measured in chondrocytes isolated from involved and uninvolved areas of OA cartilage and from normal human chondrocytes, after treatment with doxycycline, TGFβ1, and PMA. Results. Chondrocytes isolated from cartilage immediately adjacent to the OA lesion had, on average, 1.8-3.9- fold higher basal levels of MMP mRNA. These cells down-regulated collagenase proteins and mRNA upon incubation with TGFβ1. In contrast, chondrocytes from areas located more distant from the macroscopic lesion increased MMP-13 mRNA, while MMP-1 and MMP-8 decreased after stimulation with TGFβ1. Discoordinate regulation was observed after stimulation with PMA, with an increase in MMP- 1 and MMP-8 but a decrease in MMP-13. Incubation of OA chondrocytes with doxycycline (1-10 μg/ml), at pharmacologically achievable levels, decreased levels of mRNA of all 3 collagenases, but not G3PDH. In addition, doxycycline inhibited the increase in mRNA for these enzymes in normal chondrocytes stimulated with tumor necrosis factor α. Conclusion. These findings suggest that regulation of MMP-1, MMP-8, and MMP-13 in OA chondrocytes, although mediated by differing pathways, can be decreased by treatment with doxycycline at low concentrations. Our data provide a rationale for the use of doxycycline in the treatment of OA.

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