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

Abstract

In an attempt to identify the histological properties of the klotho-deficient (kl/kl) bone matrix, bone mineralization and the localization of Ca 2+ -binding bone matrix proteins -osteocalcin, dentin matrix protein-1 (DMP-1) and matrix Gla protein (MGP) -were examined in kl/kl tibiae.While a widespread osteocalcin staining could be verified in the wild-type bone matrix, localization of the same protein in kl/kl tibiae seemed rather restricted to osteocytes with only a faint staining of the whole bone matrix. In wild-type mice, MGP immunoreactivity was present at the junction between the epiphyseal bone and cartilage, and at the insertion of the cruciate ligaments. In kl/kl mice, however, MGP was seen around the cartilaginous cores of the metaphyseal trabeculae and in the periphery of some cells of the bone surface. DMP-1 was identified in the osteocytic canalicular system of wild-type tibiae, but in kl/kl tibiae this protein was mostly found in the osteocytic lacunae and in the periphery of some cells of the bone surface.Mineralization of the kl/kl bone seemed somewhat defective, with broad unmineralized areas within its matrix. In these areas, mineralized osteocytes along with their lacunae and osteocytic cytoplasmic processes were found to have intense osteocalcin and DMP-1 staining. Taken together, it might be that the excessive production of Ca 2+ -binding molecules such as osteocalcin and DMP-1 by osteocytes concentrates mineralization around such cells, disturbing the completeness of mineralization in the kl/kl bone matrix. words

Alteration in serum klotho levels in anorexia nervosa patients

“…Approximately 85% of women with AN have bone mineral density (BMD) values more than one SDS below an agecomparable mean [6]. Klotho is involved in bone mineralization [38] and kl/kl mice show a low-turnover osteoporosis with a decreased number of osteoblasts and osteoclasts and markedly reduced bone formation [7,37]. In keeping with these findings we found in the present study that klotho levels correlate with lumbar BMD z-score and with ALP levels.…”

<b>Chronological immunolocalization of sclerostin and FGF23 in the mouse metaphyseal trabecular and cortical </b><b>bone </b>

“…We have previously examined bone mineralization in kl/kl mice in which the promoter region of αKlotho gene was disrupted and the transcription activities were extremely reduced. As a consequence, despite the high concentration of phosphate and calcium ions, defective bone mineralization was observed, indicating the possible mechanism of FGF23 signaling in autocrine/paracrine manner without mediating serum concentration of phosphate and calcium ions (30). If so, since Fgf23 and Fgfr1c/αKlotho are shown to be expressed in the fetal and neonatal stages, it is of interest to examine what happens in fetal/neonatal bones of kl/kl mice, αKlotho −/− mice and intense TNAP-immunoreactivity until 8 weeksold, while sclerostin-immunoreactivity was hardly seen until 4 weeks-old, and then, came to be apparent after 8 weeks-old of age (see Figs.…”

The Connotation of Kidney Stores Essence Theory and Kidney Endocrine Substance

“…Obviously, the role of α-klotho is very similar to the TCM theory of "kidneys essence generating marrow and producing blood." Modern medical research has elucidated that α-klotho deficiency causes bone matrix protein distribution changes and calcification defect [40]; and participates in calcium and phosphorus metabolism [41]. α-Klotho also regulates the expression of vitamin D receptor [42].…”