Klotho expression in osteocytes regulates bone metabolism and controls bone formation

Abstract

Osteocytes within the mineralized bone matrix control bone remodeling by regulating osteoblast and osteoclast activity. Osteocytes express the aging suppressor Klotho, but the functional role of this protein in skeletal homeostasis is unknown. Here we identify Klotho expression in osteocytes as a potent regulator of bone formation and bone mass. Targeted deletion of Klotho from osteocytes led to a striking increase in bone formation and bone volume coupled with enhanced osteoblast activity, in sharp contrast to what is observed in Klotho hypomorphic (kl/kl) mice. Conversely, overexpression of Klotho in cultured osteoblastic cells inhibited mineralization and osteogenic activity during osteocyte differentiation. Further, the induction of chronic kidney disease with high-turnover renal osteodystrophy led to downregulation of Klotho in bone cells. This appeared to offset the skeletal impact of osteocyte-targeted Klotho deletion. Thus, our findings establish a key role of osteocyte-expressed Klotho in regulating bone metabolism and indicate a new mechanism by which osteocytes control bone formation.

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

“…First, we examined full-length (mKl 135 ) and alternatively spliced Kl (sKl 70 ) message expression in different tissues in wild-type and Kl Tg mice by real-time reverse transcription PCR (RT-PCR) (1). Endogenous mKl 135 in wild-type mice was highly expressed in the kidney; low levels of mKl 135 transcripts were also detected in bone and bone marrow (50,51), as well as in heart, spleen, and liver ( Figure 1A). In spite of the wide tissue expression of hEF1a promoter, we observed significant increases of mKl 135 transcripts, which represents the combination of the transgene and endogenous gene, only in the kidney and bone of Kl Tg mice compared with wild-type mice ( Figure 1A).…”

“…In this regard, increased circulating sKL 130 in humans caused by a de novo translocation with a breakpoint adjacent to the KL gene leads to elevations in FGF23 levels (49), suggesting that sKL 130 may stimulate FGF23 production. Although conditional deletion of Kl in osteoblasts and osteocytes has no effects on Fgf23 expression in bone (50,51), overexpression of sKl 130 (Kl1 and Kl2) stimulates Fgf23 expression in osteoblasts (52).…”

Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters

“…In addition to the kidney and parathyroids, αKlotho is also present in osteocytes and osteoblasts, which regulates FGF23 synthesis [46, 50]. To date, there is no evidence showing αKlotho presence in intestinal epithelium, another crucial organ regulating Pi absorption.…”

Insulin suppresses the production of fibroblast growth factor 23 (FGF23)

“…In the parathyroid gland, FGF23 suppresses the formation of parathyroid hormone (PTH) (3). All these endocrine effects of FGF23 are mediated by a membrane receptor that is made up of fibroblast growth factor receptor 1 csplicing form (FGFR1c) and membrane-anchored Klotho (1,4). Apart from membrane Klotho, a soluble form exists (sKlotho) that itself exerts several endocrine effects.…”