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Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient miceGamma-glutamyl transpeptidase (GGT) is a widely distributed ectopeptidase responsible for the degradation of glutathione in the gamma-glutamyl cycle. This cycle is implicated in the metabolism of cysteine, and absence of GGT causes a severe intracellular decrease in this amino acid. GGT-deficient (GGT-/-) mice have multiple metabolic abnormalities and are dwarf. We show here that this latter phenotype is due to a decreased of the growth plate cartilage total height resulting from a proliferative defect of chondrocytes. In addition, analysis of vertebrae and tibiae of GGT-/- mice revealed a severe osteopenia. Histomorphometric studies showed that this low bone mass phenotype results from an increased osteoclast number and activity as well as from a marked decrease in osteoblast activity. Interestingly, neither osteoblasts, osteoclasts, nor chondrocytes express GGT, suggesting that the observed defects are secondary to other abnormalities. N-acetylcysteine supplementation has been shown to reverse the metabolic abnormalities of the GGT-/- mice and in particular to restore the level of IGF-1 and sex steroids in these mice. Consistent with these previous observations, N-acetylcysteine treatment of GGT-/- mice ameliorates their skeletal abnormalities by normalizing chondrocytes proliferation and osteoblastic function. In contrast, resorbtion parameters are only partially normalized in GGT-/- N-acetylcysteine-treated mice, suggesting that GGT regulates osteoclast biology at least partly independently of these hormones. These results establish the importance of cysteine metabolism for the regulation of bone remodeling and longitudinal growth.
Document ID
20040087631
Document Type
Reprint (Version printed in journal)
External Source(s)
Authors
Levasseur, Regis (Baylor College of Medicine One Baylor Plaza, Houston, TX 77030, United States)
Barrios, Roberto
Elefteriou, Florent
Glass, Donald A 2nd
Lieberman, Michael W.
Karsenty, Gerard
Date Acquired
August 21, 2013
Publication Date
July 1, 2003
Publication Information
Publication: Endocrinology
Volume: 144
Issue: 7
ISSN: 0013-7227
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: R01 DK 58883
CONTRACT_GRANT: R01 ES 07827
Distribution Limits
Public
Copyright
Other
Keywords
NASA Discipline Regulatory Physiology
Non-NASA Center