The growth plate sparing effects of the selective glucocorticoid receptor modulator, AL-438.
Long-term use of glucocorticoids (GC) can cause growth retardation in children due to their actions on growth plate chondrocytes. AL-438, a non-steroidal anti-inflammatory agent that acts through the glucocorticoid receptor (GR) retains full anti-inflammatory efficacy but has reduced negative effects on osteoblasts compared to those elicited by prednisolone (Pred) or dexamethasone (Dex). We have used the murine chondrogenic ATDC5 cell line to compare the effects of AL-438 with those of Dex and Pred on chondrocyte dynamics. Dex and Pred caused a reduction in cell proliferation and proteoglycan synthesis, whereas exposure to AL-438 had no effect. LPS-induced IL-6 production in ATDC5 cells was reduced by Dex or AL-438, showing that AL-438 has similar anti-inflammatory efficacy to Dex in these cells. Fetal mouse metatarsals grown in the presence of Dex were shorter than control bones whereas AL-438 treated metatarsals paralleled control bone growth. These results indicate that the adverse effects Dex or Pred have on chondrocyte proliferation and bone growth were attenuated following AL-438 exposure, suggesting that AL-438 has a reduced side effect profile on chondrocytes compared to other GCs. This could prove important in the search for new anti-inflammatory treatments for children.
Owen
H C
HC
Bone Biology Group, Roslin Institute, Edinburgh, UK. helen.owen@bbsrc.ac.uk
Miner
J N
JN
Ahmed
S F
SF
Farquharson
C
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001846:Bone Development / Q000187:drug effects*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology; D006130:Growth Disorders / Q000139:chemically induced; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D011239:Prednisolone / Q000009:adverse effects / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism
C476829:10-methoxy-5-(2-propenyl)-2,5-dihydro-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinoline; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D005938:Glucocorticoids; D015850:Interleukin-6; D011804:Quinolines; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D011239:Prednisolone