title: Insulin-Like Growth Factor-Independent Effects of Growth Hormone on Growth Plate Chondrogenesis and Longitudinal Bone Growth.
abstract: GH stimulates growth plate chondrogenesis and longitudinal bone growth directly at the growth plate. However, it is not clear yet whether these effects are entirely mediated by the local expression and action of IGF-1 and IGF-2. To determine whether GH has any IGF-independent growth-promoting effects, we generated (TamCart)Igf1r(flox/flox) mice. The systemic injection of tamoxifen in these mice postnatally resulted in the excision of the IGF-1 receptor (Igf1r) gene exclusively in the growth plate. (TamCart)Igf1r(flox/flox) tamoxifen-treated mice [knockout (KO) mice] and their Igf1r(flox/flox) control littermates (C mice) were injected for 4 weeks with GH. At the end of the 4-week period, the tibial growth and growth plate height of GH-treated KO mice were greater than those of untreated C or untreated KO mice. The systemic injection of GH increased the phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 5B in the tibial growth plate of the C and KO mice. In addition, GH increased the mRNA expression of bone morphogenetic protein-2 and the mRNA expression and protein phosphorylation of nuclear factor-κB p65 in both C and KO mice. In cultured chondrocytes transfected with Igf1r small interfering RNA, the addition of GH in the culture medium significantly induced thymidine incorporation and collagen X mRNA expression. In conclusion, our findings demonstrate that GH can promote growth plate chondrogenesis and longitudinal bone growth directly at the growth plate, even when the local effects of IGF-1 and IGF-2 are prevented. Further studies are warranted to elucidate the intracellular molecular mechanisms mediating the IGF-independent, growth-promoting GH effects.
authors.affiliation: Section of Endocrinology and Diabetes (S.W., F.D.L.), St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134; and Center for Translational Medicine (S.W., W.Y.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Section of Endocrinology and Diabetes (S.W., F.D.L.), St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134; and Center for Translational Medicine (S.W., W.Y.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Section of Endocrinology and Diabetes (S.W., F.D.L.), St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134; and Center for Translational Medicine (S.W., W.Y.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Luca
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2 / Q000187:drug effects / Q000235:genetics; D001842:Bone and Bones / Q000187:drug effects*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects*; D024121:Collagen Type X / Q000187:drug effects / Q000235:genetics; D013006:Growth Hormone / Q000494:pharmacology*; D006132:Growth Plate / Q000187:drug effects* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D053614:Janus Kinase 2 / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics; D051996:Transcription Factor RelA / Q000187:drug effects / Q000235:genetics
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D024121:Collagen Type X; D012333:RNA, Messenger; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone; D017526:Receptor, IGF Type 1; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2