title: Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production.
abstract: The activator protein-1 (AP-1) transcription factor complex, in particular the Fos proteins, is an important regulator of bone homeostasis. Fra-2 (Fosl2), a Fos-related protein of the AP-1 family, is expressed in bone cells, and newborn mice lacking Fra-2 exhibit defects in chondrocytes and osteoclasts. Here we show that Fra-2-deficient osteoblasts display a differentiation defect both in vivo and in vitro. Moreover, Fra-2-overexpressing mice are osteosclerotic because of increased differentiation of osteoblasts, which appears to be cell autonomous. Importantly, the osteoblast-specific osteocalcin (Oc) gene and collagen1α2 (col1α2) are transcriptional targets of Fra-2 in both murine and human bone cells. In addition, Fra-2, Oc, and col1 are expressed in stromal cells of human chondroblastic and osteoblastic osteosarcomas (Os's) as well as during osteoblast differentiation of human Os cell lines. These findings reveal a novel function of Fra-2/AP-1 as a positive regulator of bone and matrix formation in mice and humans.
authors.affiliation: Genes, Development, and Disease Group, BBVA Foundation, Cancer Cell Biology Program, Spanish National Cancer Center, E-28029 Madrid, Spain.
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.forename: Maria
authors.initials: M
authors.lastname: Jimenez
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000150:complications / Q000473:pathology; D001857:Bone Matrix / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I; D051921:Fos-Related Antigen-2 / Q000172:deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000473:pathology*; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis; D010026:Osteosclerosis / Q000150:complications / Q000473:pathology; D010641:Phenotype; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D024042:Collagen Type I; C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D018808:Transcription Factor AP-1; D015675:Osteocalcin; D003094:Collagen