title: Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice.
abstract: Family with sequence similarity 20,-member C (FAM20C) is highly expressed in the mineralized tissues of mammals. Genetic studies showed that the loss-of-function mutations in FAM20C were associated with human lethal osteosclerotic bone dysplasia (Raine Syndrome), implying an inhibitory role of this molecule in bone formation. However, in vitro gain- and loss-of-function studies suggested that FAM20C promotes the differentiation and mineralization of mouse mesenchymal cells and odontoblasts. Recently, we generated Fam20c conditional knockout (cKO) mice in which Fam20c was globally inactivated (by crossbreeding with Sox2-Cre mice) or inactivated specifically in the mineralized tissues (by crossbreeding with 3.6 kb Col 1a1-Cre mice). Fam20c transgenic mice were also generated and crossbred with Fam20c cKO mice to introduce the transgene in the knockout background. In vitro gain- and loss-of-function were examined by adding recombinant FAM20C to MC3T3-E1 cells and by lentiviral shRNA-mediated knockdown of FAM20C in human and mouse osteogenic cell lines. Surprisingly, both the global and mineralized tissue-specific cKO mice developed hypophosphatemic rickets (but not osteosclerosis), along with a significant downregulation of osteoblast differentiation markers and a dramatic elevation of fibroblast growth factor 23 (FGF23) in the serum and bone. The mice expressing the Fam20c transgene in the wild-type background showed no abnormalities, while the expression of the Fam20c transgene fully rescued the skeletal defects in the cKO mice. Recombinant FAM20C promoted the differentiation and mineralization of MC3T3-E1 cells. Knockdown of FAM20C led to a remarkable downregulation of DMP1, along with a significant upregulation of FGF23 in both human and mouse osteogenic cell lines. These results indicate that FAM20C is a bone formation "promoter" but not an "inhibitor" in mouse osteogenesis. We conclude that FAM20C may regulate osteogenesis through its direct role in facilitating osteoblast differentiation and its systemic regulation of phosphate homeostasis via the mediation of FGF23.
authors.affiliation: Department of Biomedical Sciences, Texas A&M Health Science Center, Baylor College of Dentistry, Dallas, Texas, United States of America.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Suzhen
authors.initials: S
authors.lastname: Wang
authors.forename: Changcheng
authors.initials: C
authors.lastname: Li
authors.forename: Tian
authors.initials: T
authors.lastname: Gao
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Rangiani
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.forename: Jianjun
authors.initials: J
authors.lastname: Hao
authors.forename: Anne
authors.initials: A
authors.lastname: George
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Lu
authors.forename: Jay
authors.initials: J
authors.lastname: Groppe
authors.forename: Baozhi
authors.initials: B
authors.lastname: Yuan
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Chunlin
authors.initials: C
authors.lastname: Qin
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000002:abnormalities; D006801:Humans; D059630:Mesenchymal Stem Cells; D051379:Mice; D018345:Mice, Knockout; D009804:Odontoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C509696:FAM20C protein, mouse; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23