title: Comparison of the skeletal effects induced by daily administration of PTHrP (1-36) and PTHrP (107-139) to ovariectomized mice.
abstract: We here compared the changes induced by subcutaneous injection of PTHrP (1-36) or PTHrP (107-139) (80 µg/kg/day, 5 days/week for 4 or 8 weeks) in bone histology and bone remodeling factors, and in bone marrow cells (BMCs) ex vivo, in ovariectomized (OVX) mice. We also examined the osteogenic effects of these peptides in mouse mesenchymal C3H10T1/2 cells under oxidative stress condition in vitro, which recapitulates the effects of OVX. We confirmed that PTHrP (1-36) exerts bone anabolic actions, as assessed by bone histology and osteoblast differentiation markers in the long bones and plasma from OVX mice. PTHrP (107-139) was also efficient in stimulating several bone formation parameters, and it dramatically decreased bone resorption markers. Moreover, both PTHrP peptides modulate DKK-1 and Sost/sclerostin in osteoblast-like UMR-106 cells highly expressing these Wnt pathway inhibitors, related to their osteogenic action in this in vivo scenario. Administration of either PTHrP peptide improved osteogenic differentiation in BMCs from OVX mice ex vivo and in mouse mesenchymal C3H10T1/2 cells under oxidative stress condition in vitro. These data demonstrate that PTHrP (1-36) and PTHrP (107-139) can exert similar osteogenic effects in the appendicular skeleton of OVX mice. Our results suggest that these effects might occur in part by modulating the Wnt pathway. These findings lend credence to the notion that the osteogenic action of PTHrP (107-139) is likely a consequence of its anti-resorptive and anabolic features, and further support the usefulness of PTHrP (1-36) as a bone anabolic peptide in the setting of estrogen-depletion.
authors.affiliation: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Luis Fernández
authors.initials: LF
authors.lastname: de Castro
authors.forename: Daniel
authors.initials: D
authors.lastname: Lozano
authors.forename: Sergio
authors.initials: S
authors.lastname: Portal-Núñez
authors.forename: Marta
authors.initials: M
authors.lastname: Maycas
authors.forename: Mónica
authors.initials: M
authors.lastname: De la Fuente
authors.forename: José R
authors.initials: JR
authors.lastname: Caeiro
authors.forename: Pedro
authors.initials: P
authors.lastname: Esbrit
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects* / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics / Q000517:prevention & control; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D007279:Injections, Subcutaneous; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501127:Dkk1 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D012333:RNA, Messenger; C486030:Sost protein, mouse; C079957:parathyroid hormone-related peptide (1-36); C071097:parathyroid hormone-related protein (107-139)