Pro-inflammatory stimulation of meniscus cells increases production of matrix metalloproteinases and additional catabolic factors involved in osteoarthritis pathogenesis

Osteoarthritis Cartilage. 2014 Feb;22(2):264-74. doi: 10.1016/j.joca.2013.11.002. Epub 2013 Dec 4.

Abstract

Objective: Meniscus injury increases the risk of osteoarthritis; however, the biologic mechanism remains unknown. We hypothesized that pro-inflammatory stimulation of meniscus would increase production of matrix-degrading enzymes, cytokines and chemokines which cause joint tissue destruction and could contribute to osteoarthritis development.

Design: Meniscus and cartilage tissue from healthy tissue donors and total knee arthroplasties (TKAs) was cultured. Primary cell cultures were stimulated with pro-inflammatory factors [IL-1β, IL-6, or fibronectin fragments (FnF)] and cellular responses were analyzed by real-time PCR, protein arrays and immunoblots. To determine if NF-κB was required for MMP production, meniscus cultures were treated with inflammatory factors with and without the NF-κB inhibitor, hypoestoxide.

Results: Normal and osteoarthritic meniscus cells increased their MMP secretion in response to stimulation, but specific patterns emerged that were unique to each stimulus with the greatest number of MMPs expressed in response to FnF. Meniscus collagen and connective tissue growth factor (CTGF) gene expression was reduced. Expression of cytokines (IL-1α, IL-1β, IL-6), chemokines (IL-8, CXCL1, CXCL2, CSF1) and components of the NF-κB and tumor necrosis factor (TNF) family were significantly increased. Cytokine and chemokine protein production was also increased by stimulation. When primary cell cultures were treated with hypoestoxide in conjunction with pro-inflammatory stimulation, p65 activation was reduced as were MMP-1 and MMP-3 production.

Conclusions: Pro-inflammatory stimulation of meniscus cells increased matrix metalloproteinase production and catabolic gene expression. The meniscus could have an active biologic role in osteoarthritis development following joint injury through increased production of cytokines, chemokines, and matrix-degrading enzymes.

Keywords: Cytokine; MMP; Matrix metalloproteinase; Meniscus; Osteoarthritis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cells, Cultured
  • Chemokines / biosynthesis
  • Chemokines / genetics
  • Culture Media, Conditioned
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Diterpenes / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation Mediators / pharmacology*
  • Matrix Metalloproteinases / biosynthesis*
  • Menisci, Tibial / drug effects
  • Menisci, Tibial / metabolism*
  • Menisci, Tibial / pathology
  • Middle Aged
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology
  • Osteoarthritis, Knee / metabolism*
  • Osteoarthritis, Knee / pathology
  • Protein Array Analysis / methods
  • Real-Time Polymerase Chain Reaction / methods
  • Signal Transduction / physiology

Substances

  • Chemokines
  • Culture Media, Conditioned
  • Cytokines
  • Diterpenes
  • Inflammation Mediators
  • NF-kappa B
  • hypoestoxide
  • Matrix Metalloproteinases