title: The C-terminal fragment of parathyroid hormone-related peptide promotes bone formation in diabetic mice with low-turnover osteopaenia.
abstract: OBJECTIVE
  Current data suggest that parathyroid hormone (PTH)-related peptide (PTHrP) domains other than the N-terminal PTH-like domain contribute to its role as an endogenous bone anabolic factor. PTHrP-107-139 inhibits bone resorption, a fact which has precluded an unequivocal demonstration of its possible anabolic action in vivo. We thus sought to characterize the osteogenic effects of this peptide using a mouse model of diabetic low-turnover osteopaenia.
  
  
  METHODS
  PTHrP-107-139 was administered to streptozotocin-induced diabetic mice, with or without bone marrow ablation, for 13 days. Osteopaenia was confirmed by dual-energy X-ray absorptiometry and microcomputed tomography analysis. Histological analysis was performed on paraffin-embedded bone tissue sections by haematoxylin/eosin and Masson's staining, and tartrate-resistent acid phosphatase immunohistochemistry. Mouse bone marrow stromal cells and osteoblastic MC3T3-E1 cells were cultured in normal and/or high glucose (HG) medium. Osteogenic and adipogenic markers were assessed by real-time PCR, and PTHrP and the PTH(1) receptor protein expression by Western blot analysis.
  
  
  RESULTS
  PTHrP-107-139 reversed the alterations in bone structure and osteoblast function, and also promoted bone healing after marrow ablation without affecting the number of osteoclast-like cells in diabetic mice. This peptide also reversed the high-glucose-induced changes in osteogenic differentiation in both bone marrow stromal cells and the more differentiated MC3T3-E1 cells.
  
  
  CONCLUSIONS
  These findings demonstrate that PTHrP-107-139 promotes bone formation in diabetic mice. This mouse model and in vitro cell cultures allowed us to identify various anabolic effects of this peptide in this scenario.
authors.affiliation: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Lozano
authors.forename: L
authors.initials: L
authors.lastname: Fernández-de-Castro
authors.forename: S
authors.initials: S
authors.lastname: Portal-Núñez
authors.forename: A
authors.initials: A
authors.lastname: López-Herradón
authors.forename: S
authors.initials: S
authors.lastname: Dapía
authors.forename: E
authors.initials: E
authors.lastname: Gómez-Barrena
authors.forename: P
authors.initials: P
authors.lastname: Esbrit
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000503:physiopathology*; D001854:Bone Marrow Cells / Q000187:drug effects*; D001861:Bone Regeneration; D001862:Bone Resorption / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D010012:Osteogenesis; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D013311:Streptozocin; D017154:Stromal Cells / Q000187:drug effects
chemical_list: D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C071097:parathyroid hormone-related protein (107-139); D013311:Streptozocin