title: Treatment with N- and C-terminal peptides of parathyroid hormone-related protein partly compensate the skeletal abnormalities in IGF-I deficient mice.
abstract: Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1-36) and PTHrP (107-111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a , cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1-36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1-36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone.
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Centro Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain ; Unidad 761, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain ; Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
authors: Lourdes
authors: L
authors: Rodríguez-de la Rosa
authors: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain ; Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad, Instituto de Salud Carlos III, Madrid, Spain.
authors: Ana
authors: A
authors: López-Herradón
authors: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain ; Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad, Instituto de Salud Carlos III, Madrid, Spain.
authors: Sergio
authors: S
authors: Portal-Núñez
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Centro Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain ; Unidad 761, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain ; Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
authors: Silvia
authors: S
authors: Murillo-Cuesta
authors: Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain ; Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain ; Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad, Instituto de Salud Carlos III, Madrid, Spain.
authors: Daniel
authors: D
authors: Lozano
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Centro Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain ; Unidad 761, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain ; Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain.
authors: Rafael
authors: R
authors: Cediel
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Centro Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain ; Unidad 761, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain ; Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
authors: Isabel
authors: I
authors: Varela-Nieto
authors: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain ; Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad, Instituto de Salud Carlos III, Madrid, Spain.
authors: Pedro
authors: P
authors: Esbrit
mesh_terms: D000818:Animals; D005260:Female; D005269:Femur / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006130:Growth Disorders / Q000188:drug therapy* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000188:drug therapy* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D011859:Radiography; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C079957:parathyroid hormone-related peptide (1-36); C071784:parathyroid hormone-related protein (107-111); D007334:Insulin-Like Growth Factor I