ESPEYB15 5 Bone, Growth Plate and Mineral Metabolism Klotho in the control of osteocyte activity (1 abstracts)
5.12 Klotho expression in osteocytes regulates bone metabolism and controls bone formation
Komaba H , Kaludjerovic J , Hu DZ , Nagano K , Amano K , Ide N , Sato T , Densmore MJ , Hanai JI , Olauson H , Bellido T , Larsson TE , Baron R & Lanske B
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA; Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
To read the full abstract: Kidney Int 2017;92:599-611
Klotho was originally identified as a senescence-related protein because mice carrying hypomorphic Klotho alleles (kl/kl) develop premature aging with low bone turnover and osteoporosis. Primary function of Klotho is to form a specific receptor complex with fibroblast growth factor (FGF) receptor 1 (FGFR1) through which it mediates the biological function of FGF23, which in the kidney inhibits renal phosphate reabsorption and suppresses 1,25-dihydroxyvitamin D [1,25(OH)2D] synthesis. In chronic kidney disease, circulating FGF23 levels increase as a compensatory response to maintain a normal phosphate balance. High FGF23 in end-stage kidney disease exerts toxic effects on the cardiovascular and immune systems in a Klotho-independent manner.
Recent investigations have discovered the presence of Klotho in osteocytes (1). The functional role of Klotho in osteocytes is however poorly characterized. Here, the authors generated a mouse model using an osteocyte-specific deletion of the Klotho gene to explore the functional role of Klotho in osteocytes. Interestingly the deletion of Klotho from osteocytes resulted in a marked increase in bone formation and bone volume, along with the enhanced expression of osteoblastic marker genes at 5 weeks of age; this increase in bone volume was also observed in 12-week-old Dmp1-Klotho−/− mice. Furthermore, in vitro experiments conducted using Klotho overexpression in MC3T3.E1 cells caused the inhibition of mineralization and osteogenic activity during osteocyte differentiation, consistent with in vivo observations. These results collectively indicate that Klotho is a negative regulator of bone formation. This is in sharp contrast to kl/kl mice that exhibit low-turnover osteoporosis. Klotho in osteocytes could be a novel therapeutic target for managing primary and secondary osteoporosis in children.
1. Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE, Bellido T. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone. 2011;49(4):636-43.
Volume 15
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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