Role of parathyroid hormone-related protein in the decreased osteoblast function in diabetes-related osteopenia.
A deficit in bone formation is a major factor in diabetes-related osteopenia. We examined here whether diabetes-associated changes in osteoblast phenotype might in part result from a decrease in PTH-related protein (PTHrP). We used a bone marrow ablation model in diabetic mice by multiple streptozotocin injections. PTHrP (1-36) (100 microg/kg, every other day) or vehicle was administered to mice for 13 d starting 1 wk before marrow ablation. Diabetic mice showed bone loss in both the intact femur and the regenerating tibia on d 6 after ablation; in the latter, this was related to decreased bone-forming cells, osteoid surface, and blood vessels, and increased marrow adiposity. Moreover, a decrease in matrix mineralization occurred in ex vivo bone marrow cultures from the unablated tibia from diabetic mice. These skeletal alterations were associated with decreased gene expression (by real-time PCR) of Runx2, osterix, osteocalcin, PTHrP, the PTH type 1 receptor, vascular endothelial growth factor and its receptors, and osteoprotegerin to receptor activator of nuclear factor-kappaB ligand mRNA ratio, and increased peroxisome proliferator-activated receptor-gamma2 mRNA levels. Similar changes were induced by hyperosmotic (high glucose or mannitol) medium in osteoblastic MC3T3-E1 cells, which were mimicked by adding a neutralizing anti-PTHrP antibody or PTH type 1 receptor antagonists to these cells in normal glucose medium. PTHrP (1-36) administration reversed these changes in both intact and regenerating bones from diabetic mice in vivo, and in MC3T3-E1 cells exposed to high glucose. These findings strongly suggest that PTHrP has an important role in the altered osteoblastic function related to diabetes.
Lozano
Daniel
D
Laboratorio de Metabolismo Mineral y Oseo, Fundación Jiménez Díaz (Capio Group), Avenida. Reyes Católicos, 2, 28040 Madrid, Spain.
de Castro
Luis F
LF
Dapía
Sonia
S
Andrade-Zapata
Irene
I
Manzarbeitia
Félix
F
Alvarez-Arroyo
M Victoria
MV
Gómez-Barrena
Enrique
E
Esbrit
Pedro
P
D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001861:Bone Regeneration / Q000187:drug effects; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D015536:Down-Regulation / Q000502:physiology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D013311:Streptozocin
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; C079957:parathyroid hormone-related peptide (1-36); D013311:Streptozocin