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Interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta 1 and integrative meniscal repair: Influences on meniscal cell proliferation and migration

Arthritis Research and Therapy (2011) 13(6)
DOI: 10.1186/ar3515
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Abstract

Introduction: Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are up-regulated in injured and osteoarthritic knee joints. IL-1 and TNF-α inhibit integrative meniscal repair; however, the mechanisms by which this inhibition occurs are not fully understood. Transforming growth factor-β1 (TGF-β1) increases meniscal cell proliferation and accumulation, and enhances integrative meniscal repair. An improved understanding of the mechanisms modulating meniscal cell proliferation and migration will help to improve approaches for enhancing intrinsic or tissue-engineered repair of the meniscus. The goal of this study was to examine the hypothesis that IL-1 and TNF-α suppress, while TGF-β1 enhances, cellular proliferation and migration in cell and tissue models of meniscal repair. Methods: A micro-wound assay was used to assess meniscal cell migration and proliferation in response to the following treatments for 0, 24, or 48 hours: 0 to 10 ng/mL IL-1, TNF-α, or TGF-β1, in the presence or absence of 10% serum. Proliferated and total cells were fluorescently labeled and imaged using confocal laser scanning microscopy and the number of proliferated, migrated, and total cells was determined in the micro-wound and edges of each image. Meniscal cell proliferation was also assessed throughout meniscal repair model explants treated with 0 or 10 ng/mL IL-1, TNF-α, or TGF-β1 for 14 days. At the end of the culture period, biomechanical testing and histological analyses were also performed. Statistical differences were assessed using an ANOVA and Newman-Keuls post hoc test. Results: IL-1 and TNF-α decreased cell proliferation in both cell and tissue models of meniscal repair. In the presence of serum, TGF-β1 increased outer zone cell proliferation in the micro-wound and in the cross section of meniscal repair model explants. Both IL-1 and TNF-α decreased the integrative shear strength of repair and extracellular matrix deposition in the meniscal repair model system, while TGF-β1 had no effect on either measure. Conclusions: Meniscal cell proliferation in vivo may be diminished following joint injury due to the up-regulation of inflammatory cytokines, thereby limiting native cellular repair of meniscal lesions. Therefore, therapies that can promote meniscal cell proliferation have promise to enhance meniscal repair and improve tissue engineering strategies.

Figures

  • Table 1 Treatments for micro-wounding experiments
  • Figure 1 Serum increased total cells and cell proliferation in inner and outer zone cells. (A) Representative confocal images of the microwound from inner zone cells that were treated with 0%, 1%, 5%, or 10% serum for 48 hours after the scratch. In the confocal images, cells that have proliferated are yellow and all cells are labeled red. The scale bar is equal to 100 μm. (B) For inner zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch. (C) Representative confocal images of the micro-wound from outer zone cells that were treated with 0%, 1%, 5%, or 10% serum for 48 hours after the scratch. (D) For outer zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch.*: P < 0.01 compared to all other treatments.
  • Figure 2 IL-1 decreased cell proliferation in the wound. (A) Representative confocal images of the micro-wound from inner zone cells that were treated with 0, 0.1 ng/mL, 1 ng/mL, or 10 ng/mL IL-1 for 48 hours after the scratch. In the confocal images, cells that have proliferated are yellow and all cells are labeled red. The scale bar is equal to 100 μm. (B) For inner zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch. a: P < 0.01 compared to control at 48 hours; b: P < 0.05 compared to all other treatments at 24 hours; c: P < 0.005 compared to all other treatments; d: P < 0.05 compared to 1 ng/mL and 10 ng/mL at 48 hours. (C) Representative confocal images of the micro-wound from outer zone cells that were treated with 0, 0.1 ng/mL, 1 ng/mL, or 10 ng/mL IL-1 for 48 hours after the scratch. (D) For outer zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch.
  • Figure 3 TNF-a treatment decreased inner zone cell proliferation at the edge. (A) Representative confocal images of the micro-wound from inner zone cells that were treated with 0, 0.1 ng/mL, 1 ng/mL, or 10 ng/mL TNF-a for 48 hours after the scratch. In the confocal images, cells that have proliferated are yellow and all cells are labeled red. The scale bar is equal to 100 μm. (B) For inner zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch. (C) Representative confocal images of the micro-wound from outer zone cells that were treated with 0, 0.1 ng/mL, 1 ng/mL, or 10 ng/mL TNF-a for 48 hours after the scratch. (D) For outer zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch.
  • Figure 4 Low concentrations of TGF-b1 increased total outer zone cells in the wound. (A) Representative confocal images of the microwound from inner zone cells that were treated with 0, 0.1 ng/mL, 1 ng/mL, or 10 ng/mL TGF-b1 for 48 hours after the scratch. In the confocal images, cells that have proliferated are yellow and all cells are labeled red. The scale bar is equal to 100 μm. (B) For inner zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch. (C) Representative confocal images of the micro-wound from outer zone cells that were treated with 0, 0.1 ng/mL, 1 ng/mL, or 10 ng/mL TGF-b1 for 48 hours after the scratch. (D) For outer zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch.
  • Figure 5 In the presence of serum, IL-1 and TNF-a decreased, while TGF-b1 increased, cell proliferation. (A) Representative confocal images of the micro-wound from inner zone cells that were treated with 10% serum, 10% serum + 10 ng/mL IL-1, 10% serum + 10 ng/mL TNF-a, or 10% serum + 10 ng/mL TGF-b1 for 48 hours after the scratch. In the confocal images, cells that have proliferated are yellow and all cells are labeled red. The scale bar is equal to 100 μm. (B) For inner zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch. a: P < 0.05 compared to 10% serum at 48 hour; b: P < 0.05 compared to serum + TGF-b1 at 48 hours; c: P < 0.05 compared to serum + TNF-a at 24 hours. (C) Representative confocal images of the micro-wound from outer zone cells that were treated with 10% serum, 10% serum + 10 ng/mL IL-1, 10% serum + 10 ng/mL TNF-a, or 10% serum + 10 ng/mL TGF-b1 for 48 hours after the scratch. (D) For outer zone cells, total cells in the wound, proliferated cells in the wound, migrated cells in the wound, and proliferated cells at the edge at 24 and 48 hours are graphed as a percentage + standard error of the starting cell density at the edge of the scratch.
  • Figure 6 IL-1 and TNF-a decreased cell proliferation at the tissue surface. (A) Schematic of a meniscal repair explant, indicating the surface of the tissue that was analyzed in pink. Representative confocal images of the surface of (B) inner or (C) outer zone meniscal repair explants that were treated with 0, 10 ng/mL IL-1, 10 ng/mL TNF-a, or 10 ng/mL TGF-b1 for 14 days. In the confocal images, cells that have proliferated are yellow and all cells are labeled red. The scale bar is equal to 100 μm. Inner and outer zone explants were treated with control media and (D) 10 ng/mL IL-1, (E) 10 ng/mL TNF-a, or (F) 10 ng/mL TGF-b1 for 14 days. The data are graphed as a percentage of proliferated cells at the surface of the tissue + standard error. *: P < 0.00005 compared to control.
  • Figure 7 IL-1 and TNF-a decreased cell proliferation at the surface interface of the meniscal repair explants. (A) Schematic of a meniscal repair explant, indicating the surface interface of the tissue that was analyzed in pink, which included the interface and 50 μm of tissue on either side of the interface. Representative confocal images of the surface interface of (B) inner or (C) outer zone meniscal repair explants that were treated with 0, 10 ng/mL IL-1, 10 ng/mL TNF-a, or 10 ng/mL TGF-b1 for 14 days. In the confocal images, cells that have proliferated are yellow and all cells are labeled red. The scale bar is equal to 100 μm. Inner and outer zone explants were treated with control media and (D) 10 ng/mL IL-1, (E) 10 ng/mL TNF-a, or (F) 10 ng/mL TGF-b1 for 14 days. The data are graphed as a percentage of proliferated cells at the surface interface of the tissue + standard error. *: P < 0.005 compared to control.

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APA

Riera, K. M., Rothfusz, N. E., Wilusz, R. E., Weinberg, J. B., Guilak, F., & McNulty, A. L. (2011). Interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta 1 and integrative meniscal repair: Influences on meniscal cell proliferation and migration. Arthritis Research and Therapy, 13(6). https://doi.org/10.1186/ar3515

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