Glucocorticoids (GCs) regulate many physiological systems in the body and have potent
immunosuppressive and anti-inflammatory properties. In children prolonged
administration causes a reduction in growth, which is in part due to the direct effects they
have on the growth plate. This effect is dependent on the dose, duration and type of GCs
This thesis consists of four major types of studies each utilising different models of
growth and chondrocyte biology, which in combination strengthens the understanding 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 mouse 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. The length of the metatarsals at day 10 from
harvesting day length in the control, Dex and IGF-I bones was 50% ± 3, 42% ± 2,
(p<0.05) 99.3% ± 5(p<0.05) respectively. In contrast to Dex the effects of IGF-I were
immediate. Most importantly, it was demonstrated for the first time in vitro that IGF-I
increased the size of the hypertrophic zone, as occurs in vivo, 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
elevated IGF-I and IGFBP-2 levels raising the possibility of a state of IGF-I insensitivity,
which may explain subsequent growth failure.
In conclusion, this thesis translated the clinical observation that Dex is more potent than
Pred at inhibiting linear growth and these effects are dependent on the dose and duration
of the GC exposure as well as the chondrocyte phenotype. These negative effects of GC
can be reversed by IGF-I administration.