title: 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.
authors.affiliation: 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.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Komaba
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Jovana
authors.initials: J
authors.lastname: Kaludjerovic
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Dorothy Z
authors.initials: DZ
authors.lastname: Hu
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagano
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Amano
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ide
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Densmore
authors.affiliation: Division of Nephrology, Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Hanai
authors.affiliation: Division of Renal Medicine, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
authors.affiliation: Division of Renal Medicine, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tobias E
authors.initials: TE
authors.lastname: Larsson
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA. Electronic address: beate_lanske@hsdm.harvard.edu.
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D010011:Osteocytes / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D061251:Primary Cell Culture; D015398:Signal Transduction
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: FGF23; bone; hyperparathyroidism