Lozano Daniel, de Castro Luis F, Dapía Sonia, Andrade-Zapata Irene, Manzarbeitia Félix, Alvarez-Arroyo M Victoria, Gómez-Barrena Enrique, Esbrit Pedro
Laboratorio de Metabolismo Mineral y Oseo, Fundación Jiménez Díaz (Capio Group), Avenida. Reyes Católicos, 2, 28040 Madrid, Spain.
Endocrinology. 2009 May;150(5):2027-35. doi: 10.1210/en.2008-1108. Epub 2009 Feb 5.
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.
骨形成不足是糖尿病相关骨质减少的一个主要因素。我们在此研究了成骨细胞表型的糖尿病相关变化是否可能部分源于甲状旁腺激素相关蛋白（PTHrP）的减少。我们通过多次注射链脲佐菌素建立了糖尿病小鼠的骨髓消融模型。在骨髓消融前1周开始，给小鼠每隔一天注射PTHrP（1 - 36）（100微克/千克）或赋形剂，持续13天。糖尿病小鼠在消融后第6天，完整股骨和再生胫骨均出现骨丢失；在再生胫骨中，这与骨形成细胞、类骨质表面和血管减少以及骨髓脂肪增多有关。此外，来自糖尿病小鼠未消融胫骨的体外骨髓培养物中基质矿化减少。这些骨骼改变与Runx2、osterix、骨钙素、PTHrP、甲状旁腺激素1型受体、血管内皮生长因子及其受体以及骨保护素与核因子κB受体激活剂配体mRNA比值的基因表达（通过实时PCR）降低以及过氧化物酶体增殖物激活受体γ2 mRNA水平升高有关。在成骨MC3T3 - E1细胞中，高渗（高糖或甘露醇）培养基诱导了类似的变化，在正常葡萄糖培养基中向这些细胞添加中和性抗PTHrP抗体或甲状旁腺激素1型受体拮抗剂可模拟这些变化。在体内，给糖尿病小鼠完整和再生骨骼注射PTHrP（1 - 36）可逆转这些变化，在体外，对暴露于高糖的MC3T3 - E1细胞注射PTHrP（1 - 36）也可逆转这些变化。这些发现强烈表明，PTHrP在与糖尿病相关的成骨细胞功能改变中起重要作用。
