Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
J Clin Invest. 1999 Aug;104(3):229-37. doi: 10.1172/JCI5705.
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.
我们最近鉴定出一个新基因——klotho，它参与多种衰老表型的抑制过程。klotho基因座破坏的纯合子小鼠（kl/kl）表现出多种类似于人类衰老的病理状况。组织形态计量学分析显示，kl/kl小鼠存在低转换型骨质减少。骨形成的减少超过了骨吸收的减少，导致净骨量丢失。通过体外骨髓培养确定的成骨祖细胞数量在kl/kl小鼠中减少。此外，与野生型小鼠来源的成骨细胞相比，kl/kl小鼠来源的培养成骨细胞表现出较低的碱性磷酸酶活性和基质结节形成。只有当骨髓细胞来源于kl/kl小鼠时，骨髓细胞与成骨细胞共培养中的破骨细胞生成才会减少，而与成骨细胞的来源无关。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。我们得出结论，klotho基因表达缺陷导致成骨细胞和破骨细胞分化的独立受损，从而导致低转换型骨质减少。由于这种状态代表了人类老年性骨质疏松症的一个特征，kl/kl小鼠可被视为研究与年龄相关的骨质流失的细胞和分子机制的有用模型。
