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Title: Translational studies in growth plate research : the effect of glucocorticoids and growth factors on the growth plate
Author: Mushtaq, Talat
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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This thesis consists of four major types of studies each utilising different models of growth and chondrocyte biology, which in combination strengthens the understandings of the effects of GC and growth factors on the growing skeleton. The initial in vivo study showed that in children treated with Dexamethasone (Dex) or Prednisolone (Pred) for Acute Lymphoblastic Leukaemia, the effects of Dex on body composition were more apparent in that it was up to 18 times more potent at reducing short term linear growth than Pred. The ATDC5 chondrocyte cell line was fully characterised, which allowed a unique opportunity to study GC effects on a homogeneous population of chondrocytes at the chondrogenesis and terminal differentiation phases. The GCs caused a reduction in cell number, cell proliferation and proteoglycan content whilst stimulating chondrocyte differentiation. These effects were dose dependent and only observed during the chondrogenesis phase when the cells are rapidly dividing. Furthermore these negative effects could be partially reversed with the use of a GC receptor antagonist and completely reversed with IGF-I. These observations were further translated into increasingly physiological models of bone growth. Foetal metatarsal organ explants, where the three dimensional structure and cell connections of the growing bone remain intact, again demonstrated that Dex and IGF-I had opposite effects on bone growth. In contrast to Dex the effects of IGF-I were immediate. IGF-I increased the size of the hypertrophic zone, and this accounted for most of the increase in metatarsal length. Prenatal administration of Dex caused a reduction in birth weight and length and this difference was greater in the female mice. The growth restriction was associated with an elevated IGF-I and IGFBP-2 levels raising the possibility of a state of IGF-I insensitivity, which may explain subsequent growth failure.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available