Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production

Bözec, Aline; Bakiri, Latifa; Jiménez, María; Schinke, Thorsten; Amling, Michael; Wagner, Erwin F.

doi:10.1084/jem20710oia30

Cited by 18 publications

(24 citation statements)

References 39 publications

(49 reference statements)

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“…Fra-1 transgenic mice develop progressive osteosclerosis [11], and also exhibit severe lipodystrophy [12], whereas embryo-specific Fra-1 knockout mice show an osteopenic phenotype [13]. Importantly, transgenic mice overexpressing DFosB (a splice variant of FosB) or Fra-2, display a severe osteosclerotic phenotype that is observed in Fra-1 transgenic mice [14,15]. These observations thus suggest that Fra-1 plays an essential role in osteogenesis.…”

Section: Introductionmentioning

confidence: 89%

Osteogenic differentiation of C2C12 myogenic progenitor cells requires the Fos-related antigen Fra-1 – A novel target of Runx2

Geng

Sun³

et al. 2013

Biochemical and Biophysical Research Communications

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Section: Introductionmentioning

confidence: 89%

Osteogenic differentiation of C2C12 myogenic progenitor cells requires the Fos-related antigen Fra-1 – A novel target of Runx2

Geng

Sun³

et al. 2013

Biochemical and Biophysical Research Communications

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“…Genetic inactivation of single fos genes has no obvious effect on liver homeostasis (reviewed) and the relevance of Fos proteins to liver disease in loss‐of‐function mouse models has not been reported. Interestingly, broad ectopic expression of Fra‐1 or Fra‐2 in transgenic mice resulted in increased bone mass, but also generalized fibrosis with predominant manifestation in the liver and lung . In addition, Fra‐1 transgenic mice (Fra‐1 Tg ) developed an inflammation‐associated ductular reaction preceding liver fibrosis, suggesting an involvement of Fra‐1 in cholestatic liver disease …”

mentioning

confidence: 99%

Activator protein 1 transcription factor fos-related antigen 1 (fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism

et al. 2013

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The Activator Protein 1 (AP-1) transcription factor subunit Fos-related antigen 1 (Fra-1) has been implicated in liver fibrosis. Here we used loss-of-function as well as switchable, cell type-specific, gain-of-function alleles for Fra-1 to investigate the relevance of Fra-1 expression in cholestatic liver injury and fibrosis. Our results indicate that Fra-1 is dispensable in three well-established, complementary models of liver fibrosis. However, broad Fra-1 expression in adult mice results in liver fibrosis, which is reversible, when ectopic Fra-1 is switched off. Interestingly, hepatocyte-specific Fra-1 expression is not sufficient to trigger the disease, although Fra-1 expression leads to dysregulation of fibrosis-associated genes. Both opn and cxcl9 are controlled by Fra-1 in gain-of-function and loss-of-function experiments. Importantly, Fra-1 attenuates liver damage in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-feeding cholestatic liver injury model. Strikingly, manipulating Fra-1 expression affects genes involved in hepatic transport and detoxification, in particular glutathione S-transferases. Molecular analyses indicate that Fra-1 binds to the promoters of cxcl9 and gstp1 in vivo. Furthermore, loss of Fra-1 sensitizes, while hepatic Fra-1 expression protects from acetaminophen-induced liver damage, a paradigm for glutathionemediated acute liver failure. Conclusion: These data define a novel function of Fra-1/AP-1 in modulating the expression of detoxification genes and the adaptive response of the liver to bile acids/xenobiotic overload. (HEPATOLOGY 2014;59:261-273)

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“…This shows once again that despite the similar structures of Fra1 and Fra2, these two transcription factors have distinct target genes. (13,29,30) In patients with RA, IgG-RF forms because of an early break in B-cell tolerance. (31) RF is among the first described autoantibodies in human disease, known since the 1940s.…”

Section: Discussionmentioning

confidence: 99%

Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss

Grötsch¹,

Lux

Rombouts

et al. 2019

Journal of Bone and Mineral Research

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Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG‐rheumatoid factor (IgG‐RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG‐RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG‐RF production by plasma cells and regulates autoimmune‐mediated bone loss. Fra1 deficiency in B cells (Fra1ΔBcell) led to increased IgG1‐producing bone marrow plasma cells, enhanced IgG‐RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG‐RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T‐cell‐dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast‐mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG‐RF production and autoimmune‐mediated bone loss. © 2019 American Society for Bone and Mineral Research.

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Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production

Cited by 18 publications

References 39 publications

Osteogenic differentiation of C2C12 myogenic progenitor cells requires the Fos-related antigen Fra-1 – A novel target of Runx2

Osteogenic differentiation of C2C12 myogenic progenitor cells requires the Fos-related antigen Fra-1 – A novel target of Runx2

Activator protein 1 transcription factor fos-related antigen 1 (fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism

Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss

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