IGF-I signalling in bone growth: inhibitory actions of dexamethasone and IL-1beta.
OBJECTIVE
To determine if glucocorticoids and proinflammatory cytokines inhibit bone growth through a common mechanism involving impaired IGF-I signalling.


METHODS
IGF-I (100 ng/ml), dexamethasone (dex) (10(-6)M) and IL-1beta (10 ng/ml) with inhibitors of the PI3K (LY294002) and Erk 1/2 (PD98059 and UO126) IGF-I pathways (all 10 microM) were studied using the ATDC5 chondrocyte cell line and murine fetal metatarsal cultures.


RESULTS
IGF-I stimulated ATDC5 chondrocyte proliferation (322%; P < 0.001 versus control). Addition of PD or LY individually to IGF-I supplemented ATDC5 cultures partially reduced proliferation by 32% (P < 0.001), and 66% (P < 0.001), respectively. PD and LY in combination blocked all IGF-I stimulated ATDC5 proliferation. LY significantly reversed IGF-I stimulatory effects on metatarsal growth (P < 0.001), whereas PD and UO treatment had no effect. IGF-I induced ATDC5 proliferation was further decreased when Dex (24%; P < 0.01) or IL-1beta (33%; P < 0.001) were added to PD but not LY cultures. Metatarsal growth inhibition by LY was unaltered by Dex or IL-1beta addition.


CONCLUSIONS
Both the PI3K and Erk 1/2 pathways contributed independently to IGF-I mediated ATDC5 proliferation. However in metatarsal cultures, the Erk 1/2 pathway was not required for IGF-I stimulated growth. Dex and IL-1beta may primarily inhibit IGF-I induced bone growth through the PI3K pathway.
Macrae
Vicky E
VE
Bone Biology Group, Division of Gene Function and Development, Roslin Institute, Roslin, Midlothian, Edinburgh EH25 9PS, United Kingdom. vicky.macrae@bbsrc.ac.uk
Ahmed
S Faisal
SF
Mushtaq
Talat
T
Farquharson
Colin
C
D000818:Animals; D001846:Bone Development / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008682:Metatarsal Bones / Q000187:drug effects / Q000196:embryology; D051379:Mice; D009924:Organ Culture Techniques; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D053583:Interleukin-1beta; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone