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The Fos-related antigen Fra-1 is an activator of bone matrix formation.

ABSTRACT: Ectopic expression of the transcription factor Fra-1 in transgenic mice leads to osteosclerosis, a bone disorder characterized by increased bone mass. The molecular basis for this phenotype is unknown and Fra-1 functions cannot be studied by a conventional loss-of-function approach, since fra-1-knockout mice die in utero likely due to placental defects. Here we show that the lethality of fra-1-knockout mice can be rescued by specific deletion of Fra-1 only in the mouse embryo and not in the placenta. Mice lacking Fra-1 (fra-1(delta/delta)) are viable and develop osteopenia, a low bone mass disease. Long bones of fra-1(delta/delta) mice appear to have normal osteoclasts but express reduced amounts of bone matrix components produced by osteoblasts and chondrocytes such as osteocalcin, collagen1a2 and matrix Gla protein. The gene for matrix Gla protein seems to be a specific target of Fra-1 since its expression was markedly increased in the long bones of fra-1-transgenic mice. These results uncover a novel function of Fra-1 in regulating bone mass through bone matrix production by osteoblasts and chondrocytes.

SUBMITTER: Eferl R

PROVIDER: S-EPMC514946 | biostudies-other | 2004 Jul

REPOSITORIES: biostudies-other

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Tissue-specific transgenic knockdown of Fos-related antigen 2 (Fra-2) expression mediated by dominant negative Fra-2.

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Project description:Dysfunction of T helper 17 (Th17) cells leads to chronic inflammatory disorders. Signal transducer and activator of transcription 3 (STAT3) orchestrates the expression of proinflammatory cytokines and pathogenic cell differentiation from interleukin (IL)-17-producing Th17?cells. However, the pathways mediated by STAT3 signaling are not fully understood. Here, we observed that Fos-related antigen 1 (FRA1) and JUNB are directly involved in STAT3 binding to sites in the promoters of Fosl1 and Junb. Promoter binding increased expression of IL-17 and the development of Th17?cells. Overexpression of Fra1 and Junb in mice resulted in susceptibility to collagen-induced arthritis and an increase in Th17?cell numbers and inflammatory cytokine production. In patients with rheumatoid arthritis, FRA1 and JUNB were colocalized with STAT3 in the inflamed synovium. These observations suggest that FRA1 and JUNB are associated closely with STAT3 activation, and that this activation leads to Th17?cell differentiation in autoimmune diseases and inflammation.

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Restraint-induced fra-2 and c-fos expression in the rat forebrain: relationship to stress duration.

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Isolation and characterization of fra-2, an additional member of the fos gene family.

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Fra-1 and c-Fos N-Terminal Deletion Mutants Impair Breast Tumor Cell Proliferation by Blocking Lipid Synthesis Activation.

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