Growth hormone (GH) regulates both bone growth and remodeling, but it is unclear whether these actions are mediated directly by the GH receptor (GHR) and/or IGF-I signaling. The actions of GH are transduced by the Jak/Stat signaling pathway via Stat5, which is thought to regulate IGF-I expression. To determine the respective roles of GHR and IGF-I in bone growth and remodeling, we examined bones of wild-type, GHR knockout (GHR–/–), Stat5ab–/–, and GHR–/– mice treated with IGF-I. Reduced bone growth in GHR–/– mice, due to a premature reduction in chondrocyte proliferation and cortical bone growth, was detected after 2 weeks of age. Additionally, although trabecular bone volume was unchanged, bone turnover was significantly reduced in GHR–/– mice, indicating GH involvement in the high bone-turnover level during growth. IGF-I treatment almost completely rescued all effects of the GHR–/– on both bone growth and remodeling, supporting a direct effect of IGF-I on both osteoblasts and chondrocytes. Whereas bone length was reduced in Stat5ab–/– mice, there was no reduction in trabecular bone remodeling or growth-plate width as observed in GHR–/– mice, indicating that the effects of GH in bone may not involve Stat5 activation.
Natalie A. Sims, Philippe Clément-Lacroix, Francesca Da Ponte, Yasmina Bouali, Nadine Binart, Richard Moriggl, Vincent Goffin, Karen Coschigano, Martine Gaillard-Kelly, John Kopchick, Roland Baron, Paul A. Kelly