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Role of Parathyroid Hormone-Related Protein in the Decreased Osteoblast Function in Diabetes-Related Osteopenia

Laboratorio de Metabolismo Mineral y Óseo (D.L., L.F.d.C., I.A.-Z., M.V.A.-A., P.E.), Departamentos de Traumatología (E.G.-B.) and Anatomía Patológica (F.M.), Fundación Jiménez Díaz (Capio Group), 28040 Madrid; and Trabeculae (S.D.), Empresa de Base Tecnológica, S.L., 32900 San Cibrao das Viñas, Ourense, Spain

Address all correspondence and requests for reprints to: P. Esbrit, Ph.D., Laboratorio de Metabolismo Mineral y Óseo, Fundación Jiménez Díaz (Capio Group), Avenida. Reyes Católicos, 2, 28040 Madrid, Spain. E-mail: pesbrit{at}fjd.es.

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 µg/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-B ligand mRNA ratio, and increased peroxisome proliferator-activated receptor-2 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.