title: Bone mineralization is regulated by signaling cross talk between molecular factors of local and systemic origin: the role of fibroblast growth factor 23.
abstract: Body phosphate homeostasis is regulated by a hormonal counter-balanced intestine-bone-kidney axis. The major systemic hormones involved in this axis are parathyroid hormone (PTH), 1,25-dihydroxyvitamin-D, and fibroblast growth factor-23 (FGF23). FGF23, produced almost exclusively by the osteocytes, is a phosphaturic hormone that plays a major role in regulation of the bone remodeling process. Remodeling composite components, bone mineralization and resorption cycles create a continuous influx-efflux loop of the inorganic phosphate (Pi) through the skeleton. This "bone Pi loop," which is formed, is controlled by local and systemic factors according to phosphate homeostasis demands. Although FGF23 systemic actions in the kidney, and for the production of PTH and 1,25-dihydroxyvitamin-D are well established, its direct involvement in bone metabolism is currently poorly understood. This review presents the latest available evidence suggesting two aspects of FGF23 bone local activity: (a) Regulation of FGF23 production by both local and systemic factors. The suggested local factors include extracellular levels of Pi and pyrophosphate (PPi), (the Pi/PPi ratio), and another osteocyte-derived protein, sclerostin. In addition, 1,25-dihydroxyvitamin-D, synthesized locally by bone cells, may contribute to regulation of FGF23 production. The systemic control is achieved via PTH and 1,25-dihydroxyvitamin-D endocrine functions. (b) FGF23 acts as a local agent, directly affecting bone mineralization. We support the assumption that under balanced physiological conditions, sclerostin, by para- autocrine signaling, upregulates FGF23 production by the osteocyte. FGF23, in turn, acts as a mineralization inhibitor, by stimulating the generation of the major mineralization antagonist-PPi.
authors.affiliation: Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Sapir-Koren
authors.forename: Gregory
authors.initials: G
authors.lastname: Livshits
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000235:genetics*; D011756:Diphosphates / Q000378:metabolism; D025461:Feedback, Physiological; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D015398:Signal Transduction; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D011756:Diphosphates; C000717427:FGF23 protein, human; D005819:Genetic Markers; D010281:Parathyroid Hormone; D010710:Phosphates; C422903:SOST protein, human; D014807:Vitamin D; C107241:diphosphoric acid; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23
keywords: FGF23; PPi; PTH; bone mineralization; extracellular Pi; sclerostin; vitamin D