Disease relevance of Kl

• Klotho gene mutant mice (klotho mice, also called kl/kl) exhibit osteopetrosis in the metaphysis of femora and tibiae and die within 3 months [1].
• Klotho mutant mouse (kl-/-), a mouse model for human aging, exhibits various phenotypes in a wide range of organs including arteriosclerosis, neural degeneration, skin and gonadal atrophy, pulmonary emphysema, calcification of soft tissues, and cognition impairment [2].
• In the present study, we analyzed the gene expression of plasminogen activator inhibitor-1 (PAI-1), a key molecule in the development of thrombosis, in a murine model of aging, klotho mutant ( kl/kl) mice [3].
• We propose the contribution of an aging-suppressing gene, klotho, as a novel systemic factor, as a mouse deficient in the klotho gene exhibits multiple aging phenotypes including osteopenia with a low bone turnover [4].
• Klotho protein deficiency leads to overactivation of mu-calpain [5].

High impact information on Kl

• We have generated a line of mutant mouse that lacks betaKlotho, a protein that structurally resembles Klotho [6].
• We recently identified a new gene, klotho, which is involved in the suppression of multiple aging phenotypes [7].
• 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 [7].
• Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia [7].
• Studies of the mutant mouse, klotho, showing premature aging, raise a possibility that mammals have an "anti-aging hormone." A decrease of cell proliferation ability caused by the telomeres is also tightly linked to senescence [8].

Biological context of Kl

• Because Klotho induces IGF-1 and insulin resistance, these findings appear to contradict previous evidence for increased life span of dwarf mice with reduced IGF-1 and insulin levels and enhanced insulin sensitivity [9].
• These findings suggest that this deterioration in the vitamin D endocrine system may result in many of the phenotypes in kl-/- mice through effects of increased levels of calcium and phosphorus and 1,25-(OH)2D [10].
• Klotho protein may participate in calcium and phosphorus homeostasis via the regulation of the 1,25-(OH)2D signaling pathway [10].
• Furthermore, the normal genetic responses to administered 1,25-(OH)2D3, such as down-regulation of the 25-hydroxyvitamin D 1alpha-hydroxylase gene and up-regulation of 24-hydroxylase and VDR genes, were apparently impaired in kl-/- mice [10].
• Therefore, the pathway downstream after generation of second messengers following stimulation of PTH (such as the sorting of transporters of Ca absorption) might be impaired by disruption of the Klotho gene [11].

Anatomical context of Kl

• 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 [1].
• In brain, Klotho proteins were localized at choroid plexus, where the proteins were dominantly localized at the apical plasma membrane of ependymal cells [2].
• In kl-/- brain, reduction of synapses was evident in hippocampus, suggesting a role of Klotho as a humoral factor in cerebrospinal fluid [2].
• Klotho proteins in kidney localized at distal renal tubules [2].
• Klotho mRNA, however, is expressed only in brain, kidney, reproductive organs, pituitary gland, and parathyroid gland [2].

Associations of Kl with chemical compounds

• Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene [10].
• The expression of 25-hydroxyvitamin D 1alpha-hydroxylase gene, the key enzyme of vitamin D metabolism, was also greatly enhanced in kidneys of kl-/- mice [10].
• Defect in parathyroid-hormone-induced luminal calcium absorption in connecting tubules of Klotho mice [11].
• Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits [12].
• Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides [13].

Physical interactions of Kl

• Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span [14].

Regulatory relationships of Kl

• Our findings suggest that the klotho gene inhibited the differentiation of the granular duct from the striated duct due to the repression and/or down-regulation of sexual and growth hormones [15].

Other interactions of Kl

• 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) [1].
• Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein [16].
• Serum concentrations of calcitonin and PTH of kl-/- mice were normally up- and down-regulated, respectively, in response to the high levels of calcium [10].
• Feeding of a low-P(i) diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice [17].
• Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, "Klotho" mouse [3].

Analytical, diagnostic and therapeutic context of Kl

• 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 [1].
• The klotho mouse is an animal model that prematurely shows phenotypes resembling human aging [5].
• Transplantation of klotho ovaries to wild-type mice resulted in the ability to bear offspring [18].
• Renal expression of klotho was assessed by real-time PCR or Western blotting [19].
• Blood flow recovery as assessed by laser doppler perfusion imaging and angiogenesis as assessed by density of PECAM-1/CD31-positive positive capillaries were markedly impaired in mice heterozygously deficient for the klotho gene (both <0.05) [20].

References