Damage and recovery of the bone growth mechanism in young rats following 5-fluorouracil acute chemotherapy.
Chemotherapy-induced bone growth arrest and osteoporosis are significant problems in paediatric cancer patients, and yet how chemotherapy affects bone growth remains unclear. This study characterised development and resolution of damage caused by acute chemotherapy with antimetabolite 5-fluorouracil (5-FU) in young rats in the growth plate cartilage and metaphyseal bone, two important tissues responsible for bone lengthening. In metaphysis, 5-FU induced apoptosis among osteoblasts and preosteoblasts on days 1-2. In growth plate, chondrocyte apoptosis appeared on days 5-10. Interestingly, Bax was induced prior to apoptosis and Bcl-2 was upregulated during recovery. 5-FU also suppressed cell proliferation on days 1-2. While proliferation returned to normal by day 3 in metaphysis, it recovered partially on day 3, overshot on days 5-7 and normalised by day 10 in growth plate. Histologically, growth plate heights decreased by days 4-5 and returned normal by day 10. In metaphysis, primary spongiosa height was also reduced, mirroring changes in growth plate thickness. In metaphyseal secondary spongiosa, a reduced bone volume was observed on days 7-10 as there were fewer but more separated trabeculae. Starting from day 4, expression of some cartilage/bone matrix proteins and growth factors (TGF-beta1 and IGF-I) was increased. By day 14, cellular activity, histological structure and gene expression had returned normal in both tissues. Therefore, 5-FU chemotherapy affects bone growth directly by inducing apoptosis and inhibiting proliferation at growth plate cartilage and metaphyseal bone; after the acute damage, bone growth mechanism can recover, which is associated with upregulated expression of matrix proteins and growth factors.
Xian
Cory J
CJ
Department of Orthopaedic Surgery, University of Adelaide Department of Paediatrics, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. cory.xian@adelaide.edu.au
Cool
Johanna C
JC
Pyragius
Tim
T
Foster
Bruce K
BK
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001846:Bone Development / Q000187:drug effects*; D001973:Bromodeoxyuridine; D017931:DNA Primers; D005472:Fluorouracil / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley
D017931:DNA Primers; D001973:Bromodeoxyuridine; D005472:Fluorouracil