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Itaru Kojima - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic Potential of Follistatin for Colonic Inflammation in Mice
    Gastroenterology, 2005
    Co-Authors: Taeko Dohi, Chieko Ejima, Rie Kato, Yuki I. Kawamura, Rei Kawashima, Noriko Mizutani, Yoshiaki Tabuchi, Itaru Kojima
    Abstract:

    Background & Aims: Activins belong to the transforming growth factor-β superfamily. Recent studies have shown that activin and its natural antagonist, Follistatin, are involved in tissue repair and inflammatory processes. The aim of this study was to determine whether neutralization of activins with Follistatin would have an in vivo anti-inflammatory effect in several murine models of colitis. Methods: We assessed activin levels in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid (TNBS). We subsequently tested the effects of an intraperitoneal injection of Follistatin before or after induction of TNBS colitis. We also examined the established colitis induced by oral dextran sulfate sodium (DSS) as well as the spontaneous colitis that develops in interleukin (IL)-10 gene-deficient (IL-10−/−) mice. Results: Levels of activin transcripts in the colon during the acute phase of TNBS colitis were up-regulated. Epithelial cells, infiltrating macrophages (Mϕ), and endothelial cells produced excess activin βA. Pretreatment with Follistatin increased the survival rate of mice with TNBS colitis from 33% to 82% and decreased the plasma levels of IL-6 and amyloid A. Administration of Follistatin also reduced the histologic score and tissue myeloperoxidase activity in established TNBS and DSS colitis and reduced the severity of the colitis in IL-10−/− mice. Based on results obtained from 3 mouse models and from in vitro experiments, Follistatin promoted the proliferation of colonic epithelial cells. Conclusions: Neutralization of activins by Follistatin promoted epithelial cell division and tissue repair, clearly suggesting a treatment modality for intestinal inflammation.

  • Regulation of the expression of Follistatin in rat hepatocytes
    Biochimica et biophysica acta, 1997
    Co-Authors: You-qing Zhang, Makoto Kanzaki, Hiroshi Shibata, Itaru Kojima
    Abstract:

    To elucidate the regulation of Follistatin production in the liver, we studied changes in steady-state Follistatin mRNA levels in cultured rat hepatocytes. Activin A stimulated Follistatin mRNA levels in a time- and concentration-dependent manner. The stimulatory effect of activin A on Follistatin mRNA was significant at 2 h, maximal at 6 h and declined thereafter. Incubating the cells with EGF increased Follistatin mRNA levels at 48 h and later. The EGF-induced increase in Follistatin mRNA was markedly inhibited by exogenous Follistatin in the culture medium, which blocks the action of activin A synthesized in hepatocytes, suggesting that endogenous activin A at least partly mediated the effect of EGF. We also examined the effects of transforming growth factor-beta (TGF-beta), glucagon and alpha-adrenergic agonist, phenylephrine, on Follistatin mRNA levels. TGF-beta increased the Follistatin mRNA to levels similar to those caused by activin A. Phenylephrine and glucagon also increased Follistatin mRNA levels but the effects were transient and weaker than those caused by activin A. Finally, Follistatin mRNA levels were markedly increased in remnant liver 3 h after 70% hepatectomy. The mRNA remained elevated for up to 72 h. These results indicate that the expression of mRNA for Follistatin is positively controlled by activin A, TGF-beta and other hormones or neurotransmitters. The stimulatory effect of EGF on Follistatin mRNA is mediated by activin A released from hepatocytes.

  • Stimulation of Follistatin production by epidermal growth factor in cultured rat hepatocytes.
    Biochemical and biophysical research communications, 1994
    Co-Authors: Makoto Kanzaki, You-qing Zhang, Tetsuya Mine, Itaru Kojima
    Abstract:

    Production of Follistatin in cultured rat hepatocytes was studied by measuring Follistatin release with a protein-binding assay using [125I]activin A. Follistatin was detected in conditioned medium of cultured hepatocytes. Ligand blotting using [125I]activin revealed that Follistatin released into the medium consisted of two different forms with molecular weight of approximately 40 K-Da. Epidermal growth factor (EGF) elicited dose-dependent increases in DNA synthesis and Follistatin release. Dose-response relationship for EGF-induced Follistatin release correlated well with that for EGF-induced DNA synthesis. In EGF-stimulated cells, a marked increase in DNA synthesis occurred after 48 hrs. Similarly, Follistatin release was markedly augmented after 48 hrs. Amount of cell-bound Follistatin was not changed by the treatment with EGF. These results indicate that cultured hepatocytes synthesize and release Follistatin. The activin-Follistatin system operates in cultured rat hepatocytes and may modulate DNA synthesis by altering the action of activin A.

David James Phillips - One of the best experts on this subject based on the ideXlab platform.

  • Regulation and actions of activin A and Follistatin in myocardial ischaemia-reperfusion injury.
    Cytokine, 2014
    Co-Authors: Yi Chen, David James Phillips, Christine L. Rothnie, Denise J. Spring, Edward D. Verrier, Kylie Venardos, David M. Kaye, Mark P. Hedger, Julian A. Smith
    Abstract:

    Activin A, a member of the transforming growth factor-β superfamily, is stimulated early in inflammation via the Toll-like receptor (TLR) 4 signalling pathway, which is also activated in myocardial ischaemia-reperfusion. Neutralising activin A by treatment with the activin-binding protein, Follistatin, reduces inflammation and mortality in several disease models. This study assesses the regulation of activin A and Follistatin in a murine myocardial ischaemia-reperfusion model and determines whether exogenous Follistatin treatment is protective against injury. Myocardial activin A and Follistatin protein levels were elevated following 30 min of ischaemia and 2h of reperfusion in wild-type mice. Activin A, but not Follistatin, gene expression was also up-regulated. Serum activin A did not change significantly, but serum Follistatin decreased. These responses to ischaemia-reperfusion were absent in TLR4(-/-) mice. Pre-treatment with Follistatin significantly reduced ischaemia-reperfusion induced myocardial infarction. In mouse neonatal cardiomyocyte cultures, activin A exacerbated, while Follistatin reduced, cellular injury after 3h of hypoxia and 2h of re-oxygenation. Neither activin A nor Follistatin affected hypoxia-reoxygenation induced reactive oxygen species production by these cells. However, activin A reduced cardiomyocyte mitochondrial membrane potential, and Follistatin treatment ameliorated the effect of hypoxia-reoxygenation on cardiomyocyte mitochondrial membrane potential. Taken together, these data indicate that myocardial ischaemia-reperfusion, through activation of TLR4 signalling, stimulates local production of activin A, which damages cardiomyocytes independently of increased reactive oxygen species. Blocking activin action by exogenous Follistatin reduces this damage.

  • Dissociation of angiogenesis and tumorigenesis in Follistatin- and activin-expressing tumors.
    Cancer research, 2006
    Co-Authors: Jelena Krneta, David James Phillips, Jens Kroll, Frauke Alves, Claudia Prahst, Farahnaz Sananbenesi, Christian Dullin, Sarah Kimmina, Hellmut G. Augustin
    Abstract:

    The transforming growth factor-beta superfamily member activin and its antagonist, Follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2-induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/Follistatin system during angiogenesis and tumor progression, activin- and Follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than Follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, Follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and Follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, Follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/Follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained.

  • Stimulatory effects of lipopolysaccharide on endothelial cell activin and Follistatin
    Molecular and Cellular Endocrinology, 2006
    Co-Authors: Kathryn M Wilson, A Ian Smith, David James Phillips
    Abstract:

    Abstract Activin A and its binding protein, Follistatin, are released into the circulation following acute systemic inflammation. In this study, we determined the activin and Follistatin response of ovine aortic endothelial cells to lipopolysaccharide (LPS). Exposure to LPS for 1 h, mimicking a transient inflammatory event, elicited significant increases in activin βA subunit mRNA or activin A release, with larger, more prolonged increases evident with continuous exposure. On the other hand, Follistatin increases were only evident with prolonged exposure to LPS and following increases in activin A release. While cell-associated activin A increased with LPS exposure, levels were lower than those secreted, whereas the opposite was apparent for Follistatin. In summary, our findings suggest that vascular endothelial cells, while capable of releasing activin A and Follistatin following inflammatory stimulation, are unlikely to be responsible for the rapid release of activin A in vivo following inflammatory challenge.

  • Effect of heparin administration to sheep on the release profiles of circulating activin A and Follistatin.
    The Journal of endocrinology, 2004
    Co-Authors: Kristian Lee Jones, David Morrits De Kretser, David James Phillips
    Abstract:

    Activin A and Follistatin are normally present in relatively low amounts in the circulation. Heparin administration elicits a rapid and robust release of these proteins, although this phenomenon is poorly defined. In the present studies, the response to heparin administration was evaluated in the plasma of adult ewes in terms of whether it was dose-dependent, could be neutralized, was responsive to multiple stimulation, and the nature of the activin A and Follistatin released. Activin A and Follistatin were rapidly released by heparin in a dose-dependent manner (25, 100 or 250 IU/kg), with differences in the response as adjudged by peak concentration, timing of the peak and area under the curve. The heparin response could be blocked by pretreatment with protamine; conversely protamine injection alone (2 mg/kg) elicited release of Follistatin but not activin A. Repeat administration of heparin at three-hourly intervals resulted in activin and Follistatin responses to each injection, but each subsequent stimulation increased and extended the responses, consistent with saturation of the heparin clearance mechanism. Size exclusion chromatography of plasma samples confirmed that the majority of activin and Follistatin released by heparin was a complex, whereas Follistatin released by protamine was unbound. These data are consistent with a large pool of activin A and Follistatin resident on extracellular matrices, with the rapid response implicating the vascular endothelium as the prime site of release following administration of these commonly used anticoagulant therapies.

  • Regulation of ovarian function by the TGF-beta superfamily and Follistatin.
    Reproduction (Cambridge England), 2003
    Co-Authors: Shyr-yeu Lin, John R. Morrison, David James Phillips, David Morrits De Kretser
    Abstract:

    Th er ole of Follistatin as an activin-binding protein has dominated the study of this molecule for the last 10 years. However, there is emerging evidence that Follistatin has a role in modulating the biology of other members of the transforming growth factor (TGF-) superfamily. This review summarizes the current concepts encompassing Follistatin biochemistry as well as molecules with which it is functionally associated. Moreover, the importance of the two Follistatin isoforms (Follistatin-288 and Follistatin-315) is discussed with particular emphasis on the regulation of the ovary. In addition to activin, this review discusses the functions of other members of the TGF- superfamily, for example growth differentiation factor 9 (GDF-9), bone morphogenetic protein 15 (BMP-15), BMP-6, BMP-4 and BMP-7, in the ovary, and the potential interactions between Follistatin and these growth factors. The complex network of TGF- superfamily growth factor members involved in the modulation of ovarian function and the interactions of Follistatin with these proteins is highlighted.

Hiromu Sugino - One of the best experts on this subject based on the ideXlab platform.

  • transgenic expression of a myostatin inhibitor derived from Follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice
    The FASEB Journal, 2008
    Co-Authors: Masashi Nakatani, Hiromu Sugino, Yuka Takehara, Mitsuru Matsumoto, Osamu Hashimoto, Yoshihisa Hasegawa, Tatsuya Murakami, Akiyoshi Uezumi, Shinichi Takeda, Sumihare Noji
    Abstract:

    Myostatin is a potent negative regulator of skeletal muscle growth. Therefore, myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. The known myostatin inhibitors include myostatin propeptide, Follistatin, Follistatin-related proteins, and myostatin antibodies. Although Follistatin shows potent myostatin-inhibiting activities, it also acts as an efficient inhibitor of activins. Because activins are involved in multiple functions in various organs, their blockade by Follistatin would affect multiple tissues other than skeletal muscles. In the present study, we report the characterization of a myostatin inhibitor derived from Follistatin, which does not affect activin signaling. The dissociation constants (Kd) of Follistatin to activin and myostatin are 1.72 nM and 12.3 nM, respectively. By contrast, the dissociation constants (Kd) of a Follistatin-derived myostatin inhibitor, designated FS I...

  • identification and characterization of a novel Follistatin like protein as a binding protein for the tgf β family
    Journal of Biological Chemistry, 2000
    Co-Authors: Kunihiro Tsuchida, Yoshihisa Hasegawa, Koji Y Arai, Yoji Kuramoto, Norio Yamakawa, Hiromu Sugino
    Abstract:

    Follistatin is an activin-binding protein that prevents activin from binding to its receptors and neutralizes its activity. Follistatin also binds bone morphogenetic proteins (BMPs). In this study, we report the identification of a novel Follistatin-like protein from mouse. The mouse cDNA encodes a 256-residue precursor and most likely a mouse homologue of human FLRG, which was found at the breakpoint of the chromosomal rearrangement in a B-cell line. Whereas Follistatin has three Follistatin domains, which are presumed to be growth factor binding motifs, FLRG possesses only two Follistatin domains. Northern blotting revealed that mRNAs for FLRG were abundantly expressed in heart, lung, kidney, and testis in mouse. The recombinant mouse FLRG proteins were found to have binding activity for both activin and bone morphogenetic protein-2. Like Follistatin, FLRG has higher affinity for activin than for BMP-2. The FLRG protein inhibited activin-induced and BMP-2-induced transcriptional responses in a dose-dependent manner. GlutathioneS-transferase fusion proteins encoding various regions of FLRG were produced and studied. Ligand blotting using125I-activin revealed that the COOH-terminal region containing the second Follistatin domain was able to bind activin. Our finding implies that cellular signaling by activin and BMPs is tightly regulated by multiple members of the Follistatin family.

  • Expression patterns of Follistatin and two Follistatin-related proteins during mouse development.
    The International journal of developmental biology, 2000
    Co-Authors: E. De Groot, Hiromu Sugino, A. Feijen, D Eib, An Zwijsen, Gerard J.m. Martens, A.j.m. Van Den Eijnden-van Raaij
    Abstract:

    We compared the expression patterns of Follistatin and two Follistatin-related proteins (FRP and m7365) during early mouse development. m7365 is expressed continuously during preimplantation development, in contrast to FRP and Follistatin. At early postimplantation stages, Follistatin and 7365 are expressed from E6.0, while FRP is detected from E7.5 onwards. Although there is some overlap between the expression of these genes in the primitive streak and somites, their overall expression patterns are distinct.

  • Follistatin-like immunoreactivity in the cytoplasm and nucleus of spermatogenic cells in the rat
    European journal of endocrinology, 1997
    Co-Authors: Kenji Ogawa, Hiromu Sugino, Osamu Hashimoto, Masamichi Kurohmaru, Takeo Mizutani, Yoshihiro Hayashi
    Abstract:

    Immunohistochemistry using an antiserum raised against the synthetic Follistatin peptide (residues 123‐134) was used, in the present study, to detect the stage-specific appearance of immunoreactive Follistatin in the rat testis. Follistatin immunoreactivity was not found in Sertoli and Leydig cells, while it was clearly detected in spermatogenic cells. Follistatin-like immunoreactivity was detected in the cytoplasm and nucleus of late pachytene spermatocytes. Although the reaction in the cytoplasm disappeared after meiosis, it continued to be intense in the nucleus from pachytene spermatocytes to round spermatids. This finding indicated that Follistatin or its closely related peptide produced in late pachytene spermatocytes migrates from the cytoplasm to the nucleus. We subjected rat testis homogenate to affinity chromatography on a sulfate-cellulofine and anti-Follistatin Cys (123‐134)‐ Affi-Gel Hz column followed by reverse-phase HPLC and analyzed the resulting fractions by Western blotting using Follistatin antiserum. Three major bands at 57, 45 and 39 kDa or four bands at 52, 44, 39 and 34 kDa were detected in crude preparations from rat testis homogenate, under reducing or non-reducing SDS-PAGE respectively. The protein from rat testis, which was recognized by antiFollistatin (123‐134) antiserum, exhibited a characteristic pattern for Follistatin on SDS-PAGE, i.e. slower migration under reducing conditions than under non-reducing conditions, suggesting that it was Follistatin or its closely related protein. Follistatin or its closely related protein may be a stagespecific modulator of spermatogenesis. Since Follistatin-like immunoreactivity was not found in oocytes in any stage of development from embryonic to adult rats, it may act in an event specific to spermatogenesis, such as nuclear condensation. European Journal of Endocrinology 137 523‐529

  • inhibin activin and Follistatin regulatory functions in system and cell biology
    1997
    Co-Authors: 敏博 青野, Hiromu Sugino, Wylie W Vale, Usa Serono Symposia, S Serono A Symposia, Future Views
    Abstract:

    1. Receptor Serine Kinases and Signalling by Activins and Inhibins 2. The Gene Expression of Activin Receptors in Rat Pituitary 3. Follistatin Physiology and Potential Mechanisms of Action in the Human 4. Inhibins, Activins, Follistatin and GnRH - Regulators of GOnadotropin Subunit Gene Expression 5. Inhibin and Activin as Paracine Regulators of Gonadal Function: In Vitro Model Systems 6. Production and Actions of Inhibin, Activin and Follistatin in the Pituitary and Ovary 7. Expression of Inhibin Subunits, Follistatin and Activin Receptors in Normal Testicular Cells and Testiticular Tumors 8. Inhibin, Activin, and Follistatin: Onservations on their Role in the Physiology of Pregnancy 9. Changes of Activin A Secretion in Gestational Diseases 10. Two-Site Immunoassay for Native Inhibin A 11. Ultrasensitive Enzyme Immunoassay for Inhibins and Activins 12. Immunoassays for Activin and Follistatin: Results in Normal and Diseased Subjects 13. Circulating Inhibin 14. Evaluation of Maternal Serum Inhibin as a Maker for Complicated Pregnancy 15. Production of Inhibin-Related Peptides by Ovarian Tumors 16. Plasma Inhibin and Activin in Disease 17. Activin A: A Commitment Factor in Erythroid

Lourdes Ibáñez - One of the best experts on this subject based on the ideXlab platform.

  • Circulating Follistatin in the human foetus at term birth
    Pediatric obesity, 2011
    Co-Authors: G Sebastiani, Marta Díaz, Abel López-bermejo, A Arranz, Francis De Zegher, Lourdes Ibáñez
    Abstract:

    Prenatal weight partitioning is gender specific, and infants born small for gestational age (SGA) have a lower fat mass and a lower fat-free mass than infants born appropriate for gestational age (AGA). Follistatin is an adipokine with adipogenic properties. We examined whether Follistatin circulates in the human foetus at term birth and, if so, whether cord blood Follistatin relates to birthweight and neonatal body composition. The study population was comprised of 248 term newborns (128 girls, 120 boys; 133 AGA, 115 SGA). The main outcome measures used for the study were birthweight, Follistatin and insulin in umbilical cord serum, and neonatal body composition by absorptiometry. Follistatin was detectable in all cord serum samples. Cord Follistatin concentrations were similar in girls and boys, being about 25% higher (P < 0.001) in SGA than AGA infants. In SGA infants, higher Follistatin concentrations related to lower fat mass. [corrected] Follistatin is detectable in the circulation of the human foetus at term birth. The circulating levels of Follistatin, an adipogenic adipokine, are higher in SGA than AGA infants, particularly so in SGA infants with a lower fat mass. © 2011 The Authors Pediatric Obesity © 2011 International Association for the Study of Obesity.

  • Circulating Follistatin in the human foetus at term birth
    Pediatric obesity, 2011
    Co-Authors: G Sebastiani, Marta Díaz, Abel López-bermejo, A Arranz, Francis De Zegher, Lourdes Ibáñez
    Abstract:

    Summary Background Prenatal weight partitioning is gender specific, and infants born small for gestational age (SGA) have a lower fat mass and a lower fat-free mass than infants born appropriate for gestational age (AGA). Follistatin is an adipokine with adipogenic properties. Objectives We examined whether Follistatin circulates in the human foetus at term birth and, if so, whether cord blood Follistatin relates to birthweight and neonatal body composition. Methods The study population was comprised of 248 term newborns (128 girls, 120 boys; 133 AGA, 115 SGA). The main outcome measures used for the study were birthweight, Follistatin and insulin in umbilical cord serum, and neonatal body composition by absorptiometry. Results Follistatin was detectable in all cord serum samples. Cord Follistatin concentrations were similar in girls and boys, being about 25% higher (P 

D. M. De Kretser - One of the best experts on this subject based on the ideXlab platform.

  • Follistatin attenuates radiation-induced fibrosis in a murine model.
    PLOS ONE, 2017
    Co-Authors: Helen Barbara Forrester, D. M. De Kretser, Trevor Leong, Jim Hagekyriakou, Carl Norman Sprung
    Abstract:

    Purpose Fibrosis can be a disabling, severe side effect of radiotherapy that can occur in patients, and for which there is currently no effective treatment. The activins, proteins which are members of the TGFβ superfamily, have a major role in stimulating the inflammatory response and subsequent fibrosis. Follistatin is an endogenous protein that binds the activins virtually irreversibly and inhibits their actions. These studies test if Follistatin can attenuate the fibrotic response using a murine model of radiation-induced fibrosis. Experimental design C57BL/6 mice were subcutaneously injected with Follistatin 24 hours prior to irradiation. Mice were irradiated in a 10 x 10 mm square area of the right hind leg with 35 Gy and were given Follistatin 24 hours before radiation and three times a week for six months following. Leg extension was measured, and tissue was collected for histological and molecular analysis to evaluate the progression of the radiation-induced fibrosis. Results Leg extension was improved in Follistatin treated mice compared to vehicle treated mice at six months after irradiation. Also, epidermal thickness and cell nucleus area of keratinocytes were decreased by the Follistatin treatment compared to the cells in irradiated skin of control mice. Finally, the gene expression of transforming growth factor β1 (Tgfb1), and smooth muscle actin (Acta2) were decreased in the irradiated skin and Acta2 and inhibin βA subunit (Inhba) were decreased in the irradiated muscle of the Follistatin treated mice. Conclusions Follistatin attenuated the radiation-induced fibrotic response in irradiated mice. These studies provide the data to support further investigation of the use of Follistatin to reduce radiation-induced fibrosis in patients undergoing radiotherapy for cancer.

  • Follistatin and the breast implant capsule
    Plastic and reconstructive surgery. Global open, 2017
    Co-Authors: Brett Andrew Frenkiel, D. M. De Kretser, Peter Temple-smith, Graeme Southwick
    Abstract:

    This thesis examines the effect of Follistatin treatment on inflammation and fibrosis around silicone implants in mice as well as different methods of Follistatin delivery. It establishes that a single injection of Follistatin directly around the implant at the time of silicone implant insertion and a single injection of Follistatin-impregnated hydrogel at the time of silicone implant insertion into the mice both result in a significant reduction in peri-capsular inflammation and capsular fibrosis.

  • Follistatin is induced by ionizing radiation and potentially predictive of radiosensitivity in radiation-induced fibrosis patient derived fibroblasts.
    PLoS ONE, 2013
    Co-Authors: Helen Barbara Forrester, D. M. De Kretser, Trevor Leong, Alesia Ivashkevich, Michael J. Mckay, Carl Norman Sprung
    Abstract:

    Follistatin is a potent regulator of the inflammatory response and binds to and inhibits activin A action. Activin A is a member of the TGFβ protein superfamily which has regulatory roles in the inflammatory response and in the fibrotic process. Fibrosis can occur following cell injury and cell death induced by agents such as ionizing radiation (IR). IR is used to treat cancer and marked fibrotic response is a normal tissue (non-tumour) consequence in a fraction of patients under the current dose regimes. The discovery and development of a therapeutic to abate fibrosis in these radiosensitive patients would be a major advance for cancer radiotherapy. Likewise, prediction of which patients are susceptible to fibrosis would enable individualization of treatment and provide an opportunity for pre-emptive fibrosis control and better tumour treatment outcomes. The levels of activin A and Follistatin were measured in fibroblasts derived from patients who developed severe radiation-induced fibrosis following radiotherapy and compared to fibroblasts from patients who did not. Both Follistatin and activin A gene expression levels were increased following IR and the Follistatin gene expression level was lower in the fibroblasts from fibrosis patients compared to controls at both basal levels and after IR. The major Follistatin transcript variants were found to have a similar response to IR and both were reduced in fibrosis patients. Levels of Follistatin and activin A secreted in the fibroblast culture medium also increased in response to IR and the relative Follistatin protein levels were significantly lower in the samples derived from fibrosis patients. The decrease in the Follistatin levels can lead to an increased bioactivity of activin A and hence may provide a useful measurement to identify patients at risk of a severe fibrotic response to IR. Additionally, Follistatin, by its ability to neutralise the actions of activin A may be of value as an anti-fibrotic for radiation induced fibrosis.

  • Spermatogenesis does not require the local production of Follistatin
    Reproduction (Cambridge England), 2006
    Co-Authors: Shyr-yen Lin, Martin M Matzuk, John R. Morrison, D. M. De Kretser
    Abstract:

    It has been proposed that Follistatin can modulate the actions of activins and/or other members of the transforming growth factor-beta superfamily of proteins on testicular function, since mice overexpressing Follistatin showed spermatogenic disruption. However, since mice with targeted disruption of the Follistatin gene die soon after birth, it is not feasible to determine the effect of the absence of Follistatin on testicular function using this model. To further understand the role of Follistatin on the development and maintenance of spermatogenesis, fetal testes, collected by Caesarean section at day 18 of gestation from Follistatin null mice, were transplanted to the external ear of castrated recombination activating gene 1 immunocompromised male mice. The testicular grafts were then analysed 7-8 weeks after transplantation and showed that full spermatogenesis developed in both the testes of wild-type and Follistatin null mice. This study indicates that, if Follistatin is required to modulate spermatogenic development, it is not supplied by local testicular production but by circulating Follistatin from the host mouse.

  • Localization of Follistatin in the rat testis
    Journal of reproduction and fertility, 1998
    Co-Authors: Andreas Meinhardt, Kate L Loveland, David James Phillips, Moira K O'bryan, James R. Mcfarlane, Con Mallidis, Lynda M. Foulds, D. M. De Kretser
    Abstract:

    The cellular localization of the activin-binding protein, Follistatin, in the rat testis has been a matter of some controversy with different investigators claiming that Sertoli cells, Leydig cells or germ cells are the primary cell types containing this protein. The localization of mRNA encoding Follistatin was re-examined using reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization as well as the distribution of Follistatin by immunohistochemistry. The results demonstrate that mRNA encoding Follistatin is located in many germ cells including type B spermatogonia, primary spermatocytes with the exception of the late leptotene and early zygotene stages, and spermatids at steps 1 to 11. It is also found in Sertoli cells and endothelial cells but not in Leydig cells. Immunohistochemistry, using two different antisera to Follistatin, showed that this protein was localized to spermatogonia, primary spermatocytes at all stages except the zygotene stage, spermatids at all stages and to endothelial cells and Leydig cells in the intratubular regions. The failure to detect mRNA for Follistatin in Leydig cells using RT-PCR and in situ hybridization suggests that the immunohistochemical localization in these cells reflects binding of Follistatin produced elsewhere. The widespread localization of Follistatin, taken together with its capacity to neutralize the actions of activin, may indicate that Follistatin modulates a range of testicular actions of activin, many of which remain unknown.