Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34
Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34
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DOI：
10.1172/jci24918
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发表时间：
2005-09-01
影响因子：
15.9
通讯作者：
Karaplis, AC
中科院分区：
文献类型：
--
作者：
Miao, DS;He, B;Karaplis, AC
Pthrp靶向破坏的杂合小鼠在3月龄时表现出骨体积减少和骨骼微结构变化，这表明晚期骨质疏松症。由BM前体细胞募集减少和成骨细胞凋亡增加引起的骨形成受损被确定为低骨量的潜在机制。通过Cre-LoxP技术产生的成骨细胞特异性靶向破坏Pthrp，在小鼠中重现了骨形成表型，骨形成缺陷被确认为潜在病因。每日向Pthrp（+/-）小鼠施用甲状旁腺激素（PTH 1-34）的1-34氨基末端片段导致骨骼微结构的所有参数的显著改善，超过在经处理的WT同窝仔中观察到的改善。这些发现确立了成骨细胞源性PTH相关蛋白（PTHrP）作为一种有效的内源性骨合成代谢因子的关键作用，该因子通过改变成骨细胞募集和存活来增强骨形成，并且其在骨微环境中的表达水平影响外源性PTH 1-34的治疗功效。
Mice heterozygous for targeted disruption of Pthrp exhibit, by 3 months of age, diminished bone volume and skeletal microarchitectural changes indicative of advanced osteoporosis. Impaired bone formation arising from decreased BM precursor cell recruitment and increased apoptotic death of osteoblastic cells was identified as the underlying mechanism for low bone mass. The osteoporotic phenotype was recapitulated in mice with osteoblast-specific targeted disruption of Pthrp, generated using Cre-LoxP technology, and defective bone formation was reaffirmed as the underlying etiology. Daily administration of the 1-34 amino-terminal fragment of parathyroid hormone (PTH 1-34) to Pthrp(+/-) mice resulted in profound improvement in all parameters of skeletal microarchitecture, surpassing the improvement observed in treated WT littermates. These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1-34.