Klotho-deficient mice are resistant to bone loss induced by unloading due to sciatic neurectomy

Abstract

Unloading induces bone loss as seen in experimental animals as well as in space flight or in bed-ridden conditions; however, the mechanisms involved in this phenomenon are not fully understood. Klotho mutant mice exhibit osteopetrosis in the metaphyseal regions indicating that the klotho gene product is involved in the regulation of bone metabolism. To examine whether the klotho gene product is involved in the unloading-induced bone loss, the response of the osteopetrotic cancellous bones in these mice was investigated. Sciatic nerve resection was conducted using klotho mutant (kl/kl) and control heterozygous mice (+/kl) and its effect on bone was examined by micro-computed tomography ( CT). As reported previously for wild-type mice (+/+), about 30% bone loss was induced in heterozygous mice (+/kl) by unloading due to neurectomy within 30 days of the surgery. By contrast, kl/kl mice were resistant against bone loss induced by unloading after neurectomy. Unloading due to neurectomy also induced a small but significant bone loss in the cortical bone of the mid-shaft of the femur in the heterozygous mice; no reduction in the cortical bone was observed in kl/kl mice. These results indicate that klotho mutant mice are resistant against bone loss induced by unloading due to neurectomy in both cortical and trabecular bone and indicate that klotho is one of the molecules involved in the loss of bone by unloading.

Nck1 deficiency accelerates unloading‐induced bone loss

“…Neurectomy (Ntx; unloading mouse model) induced loss in bone mass and sparse trabecular bone in the distal femora of Wt mice (Fig. 4A,B) as reported previously (Yamashita et al, 2001). The loss of Nck1 genes (Nck1–KO) further accelerated the degree of unloading‐induced sparse pattern of bone (Fig.…”

“…A total of nine Nck1–KO and nine Wt mice at the age 6 weeks were used for this study. Animals were anesthetized with sodium pentobarbital (40 µg/g body weight) a 5–6 mm segment of left sciatic nerve and femoral nerve was respected as previously described (Yamashita et al, 2001). As a control or sham side, the right sciatic nerve and femoral nerve were exposed surgically but were not rejected.…”

“…Unloading‐induced bone loss has been seen in many cases, including astronauts, long‐term bed‐ridden patients (Morey and Baylink, 1978) and tail‐suspension model of rodents (Wronski and Morey, 1982) Unloading by hindlimb immobilization due to neurectomy also induces bone loss (Turner and Bell, 1986; Wakley et al, 1988). This reduction in bone mass is caused by an initial decrease in bone formation and subsequent increase in the osteoclastic bone resorption (Weinreb et al, 1989; Murakami et al, 1994; Zeng et al, 1996; Sakai et al, 1996; Shen et al, 1997; Yamashita et al, 2001).…”

Altered distribution of bone matrix proteins and defective bone mineralization in klotho-deficient mice

“…Mice carrying mutations of klotho (kl/kl mice) grow normally until the third postnatal week, becoming less active afterwards and ultimately dying around 8-9 weeks of age [10]. The phenotype is one of osteoporosis, skin atrophy, ectopic calcifications, pulmonary emphysema, gonadal dysplasia, defective hearing, hypervitaminosis D, hypercalcemia, hyperphosphatemia [10,11], and elevated osteoprotegerin levels [12,13]. Kl/kl mice show increased renal expression of sodium phosphate cotransporter (NaPi) IIa and NaPi IIc protein, with concomitant hyperphosphatemia.…”

Phenotypic characterization of skeletal abnormalities of Osteopotentia mutant mice by micro-CT: a descriptive approach with emphasis on reconstruction techniques

“…An excellent example of a qualitative characterization of a mutant mouse model was presented by Ford-Hutchinson and co-workers [14]. However, as in other comparable studies, only threshold-dependent 3D surface reconstructions were employed to visualize skeletal pathology and no histological correlation was provided [11, 15]. While the 3D surface-rendered reconstructions give a good overview of deformities and bone shape, in general intraosseous and cortical details are not visualized.…”