title: Proportionate Dwarfism in Mice Lacking Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) Is Associated With Alterations in the Endocrine IGF-1 Pathway.
abstract: Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3, we have previously described an Hp1bp3(-/-) mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length, and organ weight. In addition to their small size, microcomputed tomography analysis showed that Hp1bp3(-/-) mice present a dramatic impairment of their bone development and structure. By 3 weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3(-/-) bone marrow and splenocytes, respectively, showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to noncell autonomous systemic cues in vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of IGF-1, the IGF receptors, and the IGF-binding proteins (IGFBPs). At 3 weeks of age, Hp1bp3(-/-) mice exhibited a 60% reduction in circulating IGF-1 and a 4-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1, and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components.
authors.affiliation: Department of Biological Chemistry (B.P.G., S.A., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Center for Clinical and Translational Research (P.T.L., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Protein Section (M.B.), Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Anatomy and Anthropology (Y.G.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Garfinkel
authors.affiliation: Department of Biological Chemistry (B.P.G., S.A., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Center for Clinical and Translational Research (P.T.L., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Protein Section (M.B.), Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Anatomy and Anthropology (Y.G.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Arad
authors.affiliation: Department of Biological Chemistry (B.P.G., S.A., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Center for Clinical and Translational Research (P.T.L., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Protein Section (M.B.), Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Anatomy and Anthropology (Y.G.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Phuong T
authors.initials: PT
authors.lastname: Le
authors.affiliation: Department of Biological Chemistry (B.P.G., S.A., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Center for Clinical and Translational Research (P.T.L., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Protein Section (M.B.), Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Anatomy and Anthropology (Y.G.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Bustin
authors.affiliation: Department of Biological Chemistry (B.P.G., S.A., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Center for Clinical and Translational Research (P.T.L., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Protein Section (M.B.), Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Anatomy and Anthropology (Y.G.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.affiliation: Department of Biological Chemistry (B.P.G., S.A., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Center for Clinical and Translational Research (P.T.L., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Protein Section (M.B.), Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Anatomy and Anthropology (Y.G.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Yankel
authors.initials: Y
authors.lastname: Gabet
authors.affiliation: Department of Biological Chemistry (B.P.G., S.A., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Center for Clinical and Translational Research (P.T.L., C.J.R.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Protein Section (M.B.), Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Anatomy and Anthropology (Y.G.), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Orly
mesh_terms: D000818:Animals; D049628:Body Size / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D001846:Bone Development / Q000235:genetics*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004392:Dwarfism / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D055114:X-Ray Microtomography
chemical_list: C000598191:HP1BP3 protein, mouse; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D009687:Nuclear Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1