Bone homeostasis in growth hormone receptor-null mice is restored by IGF-Ibut independent of Stat5

Growth hormone (GH) regulates both bone growth and remodeling, but it is un clear 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 si gnaling pathway via Stat5, which is thought to regulate IGF-I expression. T o determine the respective roles of GHR and IGF-I in bone growth and remode ling, we examined bones of wild-type, GHR knockout (GHR(-/-)), Stat5ab(-/-) , and GHR(-/-) mice treated with IGF-I. Reduced bone growth in GHR(-/-) mic e, due to a premature reduction in chondrocyte proliferation and cortical b one growth, was detected after 2 weeks of age. Additionally, although trabe cular bone volume was unchanged, bone turnover was significantly reduced in GHR(-/-) mice, indicating GH involvement in the high bone-turnover level d uring 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 S tat5ab(-/-) mice, there was no reduction in trabecular bone remodeling or g rowth-plate width as observed in GHR-/- mice, indicating that the effects o f GH in bone may not involve Stat5 activation.