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Double Mutations in Klotho and Osteoprotegerin Gene Loci Rescued Osteopetrotic Phenotype

Department of Molecular Pharmacology (T.Y., M.N.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; Department of Development Genetics (S.O.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Research Institute of Life Science (K.H.), Snow Brand Milk Products Co., Ltd., Tochigi 329-0512, Japan; Department of Pathology and Tumor Biology (Y.N.), Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and Core Research for Evolutional Science and Technology (Y.N.), Japan Science and Technology Corp., Tokyo, Japan 102-8666

Address all correspondence and requests for reprints to: Masaki Noda, Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan. E-mail: noda.mph{at}mri.tmd.ac.jp.

Klotho gene mutant mice (klotho mice, also called kl/kl) exhibit osteopetrosis in the metaphysis of femora and tibiae and die within 3 months. We previously showed by semiquantitative RT-PCR that osteoprotegerin (opg) expression levels in klotho mice were about 2-fold higher than those in wild-type mice in the bone marrow, spleen, and lung. To examine whether the high osteoprotegerin expression levels account for the osteopetrotic phenotype in the klotho homozygous mutant mice in vivo, we made double mutant mice by crossing klotho mutant and osteoprotegerin-deficient mice. Micro computed tomography analysis in the two-dimensional sagittal planes of the metaphyses and cross-sections of femoral midshaft revealed that the abnormally high fractional trabecular bone volume in klotho homozygous mice (kl/kl; 29.71%), which was about 4-fold higher compared with that of wild-type [klotho (+/+) opg (+/+)] mice (7.81%), was rescued by the coexistence of heterozygous mutation in opg gene locus (+/-; 8.36%). Single heterozygous mutation in the opg gene locus alone (without klotho mutation) did not show phenotype (trabecular bone volume, 5.84%; not significantly different from wild type). High levels of osteoprotegerin mRNA expression in the bone marrow in klotho mutant mice were reduced by the heterozygous mutation in the opg gene locus. Furthermore, high osteoprotegerin protein levels in klotho mutant mice were also reduced by the heterozygous mutations in opg gene locus. Thus, elevated levels of osteoprotegerin in mutant mice contribute at least in part to reveal the osteopetrotic phenotype in klotho mice.

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