Glucose regulation of the IGF response system in chondrocytes: induction of an IGF-I-resistant state

Abstract

Nonresponsiveness to the growth-stimulatory actions of insulin-like growth factor (IGF)-I in chondrocytes has been reported in a number of disease states associated with impaired glucose metabolism. Primary rabbit chondrocytes were investigated for changes in their IGF response system [type-I IGF receptor and IGF-binding protein (IGFBP) expression] and in their ability to mount a synthetic response to IGF-I [as35S-labeled proteoglycan ([35S]PG) production] in media containing varying ambient glucose concentrations. Whereas basal [35S]PG synthetic rate was unaffected by glucose concentration, synthetic responsiveness to IGF-I was lost in media containing <5 mmol/l glucose or in media containing a “diabetic” glucose concentration (25 mmol/l). IGFBP expression, as measured by Northern analysis of mRNA levels and Western ligand blotting of secreted protein levels, was not significantly altered in the different glucose media, nor were there any differences in the cell surface localization of IGFBPs as assessed by affinity cross-linking with 125I-labeled IGF-I, suggesting that IGFBPs do not induce the IGF-I resistance. The nonresponsiveness to IGF-I in reduced glucose occurred with 25–50% reductions in steady-state levels of IGF type-I receptor mRNA and protein. A significant correlation between IGF receptor mRNA level and synthetic response to IGF-I was observed between 0 and 10 mmol/l glucose concentrations, suggesting that the loss of responsiveness in reduced glucose is manifested at the level of transcription and/or receptor mRNA stability. In contrast, nonresponsiveness to IGF-I in chondrocytes in diabetic glucose concentrations occurred without changes in receptor mRNA and protein levels, suggesting that IGF-I resistance was due to post-ligand-binding receptor defects. It is proposed that IGF-I resistance in chondrocytes subjected to inappropriate glucose levels may constitute an important pathogenic mechanism in degenerative cartilage disorders.

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function

“…Our studies suggested that IGF-1 may rescue the diabetes-induced reduction in SERCA protein abundance and impaired -adrenergic responsiveness (Norby et al 2002(Norby et al , 2004. In addition, diabetic tissues including hearts usually display IGF-1 resistance (Rodgers et al 1995, Kelley et al 1999, Ren et al 1999a, Ren 2000, making glucose clearing by IGF-1 largely dependent on crossreaction with the insulin receptor, which requires higher levels of IGF-1 agonist.…”

Cytokine Regulation of Facilitated Glucose Transport in Human Articular Chondrocytes

“…Glucose serves as a main energy source in chondrocytes (4,5), as a main precursor for glycosaminoglycan synthesis (6, 7), and as a regulator of the cell responses to certain growth factors (44). GLUTs also participate in facilitated transport of glucosamine and N-acetylglucosamine (45,46), which can modify inflammatory responses of chondrocytes (47) and serve as efficient precursors of glycosaminoglycan synthesis (48).…”

Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes

“…In those circumstances, high extracellular glucose concentrations may counteract TGF effects and eventually those of other anabolic growth factors, such as IGF [Kelley et al, 1999], suggesting that hyperglycemia may be an initiating and/or aggravating factor linking DM to OA.…”

“…Among these, the extracellular glucose concentration, either increased or decreased, has been shown to directly affect some chondrocyte functions [Kelley et al, 1999;Richardson et al, 2003;McNulty et al, 2005]. In particular, culture of rabbit chondrocytes in either low (<5 mM) or high (25 mM) glucose concentrations decreased proteoglycan synthesis induced by the anabolic growth factor, IGF-I [Kelley et al, 1999]. Exposure to increasing glucose concentrations, dose-dependently decreased dehydroascorbate uptake by human chondrocytes [McNulty et al, 2005], which may have functional implications as dehydroascorbate is essential for collagen synthesis.…”