Role of the N- and C-terminal fragments of parathyroid-hormone-related protein as putative therapies to improve bone regeneration under high glucocorticoid treatment.
The parathyroid-hormone-related protein (PTHrP) is an important modulator of bone formation and bone remodeling. High and/or prolonged glucocorticoid (GC) treatments inhibit PTHrP expression in osteoblastic cells and bone formation and repair. We assessed the ability of the N- and C-terminal PTHrP fragments to restore the GC-altered bone regeneration after bone marrow ablation in mice. Animals were administered 3-methylprednisolone or vehicle and PTHrP (1-36) or PTHrP (107-139) every other day, beginning 4 days before marrow ablation in the tibia, and euthanized 12 days later. GC-treated mice showed in the ablated tibia a decrease in bone formation and in osteoblast and sclerostin-positive osteocyte numbers, reduced expression of osteoblastic factors, decreased osteogenesis of bone-marrow-derived cells, an increase in the numbers of multinucleated osteoclasts and adipocytes, and decreased cortical vascularization, as well as altered bone structure (measured by microcomputerized tomography) in the intact femur. These effects were reversed at least in part by either PTHrP peptide. The present novel findings support the use of both PTHrP peptides tested as putative bone regenerative therapies in GC-related bone diseases.
de Castro
Luís Fernándes
LF
Jiménez Díaz Foundation, Madrid, Spain .
Lozano
Daniel
D
Dapía
Sonia
S
Portal-Núñez
Sergio
S
Caeiro
José R
JR
Gómez-Barrena
Enrique
E
Esbrit
Pedro
P
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001861:Bone Regeneration / Q000187:drug effects* / Q000502:physiology; D001862:Bone Resorption / Q000139:chemically induced / Q000188:drug therapy; D002478:Cells, Cultured; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D023822:Tissue Engineering; D055114:X-Ray Microtomography
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C486030:Sost protein, mouse; C079957:parathyroid hormone-related peptide (1-36); C071097:parathyroid hormone-related protein (107-139); D008775:Methylprednisolone