Short-term glucocorticoid treatment of prepubertal mice decreases growth and IGF-I expression in the growth plate.
The insulin-like growth factor (IGF) system is an important mediator of postnatal longitudinal growth, and the growth inhibiting effects of glucocorticoid (GC) treatment are suggested to be due to impaired action of the IGF system. However, the precise changes of the IGFs and the IGF-binding proteins (IGFBPs) in the growth plate, occurring upon short-term GC treatment have not been characterized. Prepubertal mice treated daily with dexamethasone (DXM) for 7 days, showed significant growth inhibition of total body length and weight and weight of the liver, thymus and spleen, whereas the weight of the kidneys was not affected. Analysis of the tibial growth plate showed that the total growth plate width significantly decreased to 84.5% of control values, caused by a significant decrease in the proliferative zone. The number of proliferating cell nuclear antigen (PCNA)-positive chondrocytes in the proliferative zone decreased significantly (to 40%) and TUNEL staining showed a significant 1.6-fold increase in apoptotic hypertrophic chondrocytes. In the growth plates, both IGF-I and IGF-II, as well as IGFBP-2 mRNAs were detected, mainly in the proliferative and prehypertrophic zones. DXM treatment significantly decreased the number of chondrocytes expressing IGF-I, whereas the number of chondrocytes expressing IGF-II and IGFBP-2 were not affected. The decrease in IGF-I expression in the growth plate indicates that GC treatment affects IGF-I at the local level of the growth plate, which could contribute to the GC-induced growth retardation.
Smink
J J
JJ
Department of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands.
Gresnigt
M G
MG
Hamers
N
N
Koedam
J A
JA
Berger
R
R
Van Buul-Offers
S C
SC
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D019902:Chondrocytes / Q000737:chemistry / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000009:adverse effects* / Q000494:pharmacology; D006128:Growth / Q000187:drug effects*; D006132:Growth Plate / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000032:analysis / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012741:Sexual Maturation; D013977:Tibia
D015415:Biomarkers; D005938:Glucocorticoids; D018971:Insulin-Like Growth Factor Binding Protein 2; D018809:Proliferating Cell Nuclear Antigen; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D003907:Dexamethasone