Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia
Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia
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DOI：
10.1172/jci5705
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发表时间：
1999-08-01
影响因子：
15.9
通讯作者：
Kuro-o, M
中科院分区：
文献类型：
--
作者：
Kawaguchi, H;Manabe, N;Kuro-o, M
我们最近发现了一个新的基因klotho，它参与了多种衰老表型的抑制。klotho基因座（kl/kl）的破坏纯合子小鼠表现出多种类似人类衰老的病理条件。组织形态计量学分析显示kl/kl小鼠出现低转换骨量减少。骨形成的减少超过骨吸收，导致净骨丢失。在kl/kl小鼠中，通过离体骨髓培养确定的成骨祖细胞的数量减少。此外，来自kl/kl小鼠的培养成骨细胞显示出较低的碱性磷酸酶活性和基质结节形成比野生型小鼠。骨髓细胞和成骨细胞共培养的破骨细胞生成减少，只有当骨髓细胞来源于kl/kl小鼠独立的成骨细胞的起源。我们还发现，破骨细胞生成抑制剂骨保护素的表达在kl/kl小鼠中显著上调。我们的结论是，klotho基因表达的缺陷导致成骨细胞和破骨细胞分化的独立损害，导致低周转骨量减少。由于这种状态代表了人类老年性骨质疏松症的特征，因此kl/kl小鼠可被视为研究年龄相关性骨丢失的细胞和分子机制的有用模型。
We recently identified a new gene, klotho, which is involved in the suppression of multiple aging phenotypes. The mouse homozygous for a disruption of the klotho locus (kl/kl) exhibited multiple pathological conditions resembling human aging. Histomorphometric analysis revealed low-turnover osteopenia in kl/kl mice. The decrease in bone formation exceeded that of bone resorption, resulting in a net bone loss. The number of osteoblast progenitors determined by ex vivo bone marrow cultures was reduced in kl/kl mice. In addition, cultured osteoblastic cells derived from kl/kl mice showed lower alkaline phosphatase activity and matrix nodule formation than those from wild-type mice. Osteoclastogenesis in the coculture of marrow cells and osteoblastic cells was decreased only when marrow cells originated from kl/kl mice independently of the origin of osteoblastic cells. We also found that the expression of osteoprotegerin, an osteoclastogenesis inhibitor, was significantly upregulated in kl/kl mice. We conclude that a defect in the klotho gene expression causes the independent impairment of both osteoblast and osteoclast differentiation, leading to low-turnover osteopenia. Because this state represents a characteristic feature of senile osteoporosis in humans, kl/kl mice can be regarded as a useful model for investigating cellular and molecular mechanisms of age-related bone loss.