Nitric oxide inhibits chondrocyte response to IGF-I: Inhibition of IGF-IRβ tyrosine phosphorylation

R. K. Studer, E. Levicoff, H. Georgescu, L. Miller, D. Jaffurs, C. H. Evans

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Chondrocytes in arthritic cartilage respond poorly to insulin-like growth factor I (IGF-I). Studies with inducible nitric oxide synthase (iNOS) knockout mice suggest that NO is responsible for part of the cartilage insensitivity to IGF-I. These studies characterize the relationship between NO and chondrocyte responses to IGF-I in vitro, and define a mechanism by which NO decreases IGF-I stimulation of chondrocyte proteoglycan synthesis. Lapine cartilage slices, chondrocytes, and cartilage from osteoarthritic (OA) human knees were exposed to NO from the donors S-nitroso-N-acetylpenicillamine (SNAP) or (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate] (DETA NONOate), by transduction with adenoviral transfer of iNOS (Ad-iNOS), or by activation with interleukin-1 (IL-1). NO synthesis was estimated from medium nitrite, and proteoglycan synthesis was measured as incorporation of 35SO4. IGF-I receptor phosphorylation was evaluated with Western analysis. SNAP, DETA NONOate, endogenously synthesized NO in Ad-iNOS-transduced cells, or IL-1 activation decreased IGF-I-stimulated proteoglycan synthesis in cartilage and monolayer cultures of chondrocytes. OA cartilage responded poorly to IGF-I; however, the response to IGF-I was restored by culture with N(G)-monomethyl-L-arginine (L-NMA). IGF-I receptor phosphotyrosine was diminished in chondrocytes exposed to NO. These studies show that NO is responsible for part of arthritic cartilage/chondrocyte insensitivity to anabolic actions of IGF-I; inhibition of receptor autophosphorylation is potentially responsible for this effect.

Original languageEnglish (US)
Pages (from-to)C961-C969
JournalAmerican Journal of Physiology - Cell Physiology
Volume279
Issue number4 48-4
DOIs
StatePublished - 2000

Keywords

  • Arthritis
  • Cartilage
  • Chondrocytes
  • Insulin-like growth factor I
  • Insulin-like growth factor I receptor
  • Matrix proteoglycan synthesis
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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