Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling
Year: 2009
Type: article
Abstract: Linear growth in children is sensitive to nutritional status. Amino acids, in particular leucine, have been shown to regulate cell growth, proliferation, and differentiation through the mammalian target of rapamycin (mTOR), a nutrient-sensing protein kinase. Having recently demonstrated a role for mTOR in chondrogenesis, we hypothesized that leucine restriction, acting through mTOR, would inhibit growth plate chondrocyte proliferation and differentiation. The effect of leucine restriction was compared with that of the specific mTOR inhibitor, rapamycin. Leucine restriction produced a dose-dependent inhibition of fetal rat metatarsal explant growth. This was accounted by reduced cell proliferation and hypertrophy but not apoptosis. mTOR activity, as reflected by ribosomal protein S6 phosphorylation, was only partially inhibited by leucine restriction, whereas rapamycin abolished S6 phosphorylation. In chondrogenic ATDC5 cells, leucine restriction inhibited cell number, proteoglycan accumulation, and collagen X expression despite minimal inhibition of mTOR. Microarray analysis demonstrated that the effect of leucine restriction on ATDC5 cell gene expression differed from that of rapamycin. Out of 1,571 genes affected by leucine restriction and 535 genes affected by rapamycin, only 176 genes were affected by both. These findings indicate that the decreased chondrocyte growth and differentiation associated with leucine restriction is only partly attributable to inhibition of mTOR signaling. Thus nutrient restriction appears to directly modulate bone growth through unidentified mTOR-independent mechanisms in addition to the well-characterized mTOR nutrient-sensing pathway.
Institution: Rhode Island Hospital
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1371143496, G1414418711, COBRE for Skeletal Health and Repair, Biophysical Regulation of Chondrocyte Differentiation, G3051813480, COBRE for Skeletal Health and Repair, Novel Approaches to Understanding the Nutrient Regulation of Fetal Somatic Growth, G5503668833, Nutritional Regulation of Fetal Liver Development
OpenAlex ID: W2128777341