Determination of free follistatin levels in sera of normal subjects and patients with various diseases

Sakamoto, Yuki; Shintani, Yoshihiro; Harada, Kyoko; Abe, Masahiro; Shitsukawa, K.; Saito, Shiro

doi:10.1530/eje.0.1350345

Cited by 35 publications

(23 citation statements)

References 33 publications

(60 reference statements)

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“…In contrast, two previous smaller studies have reported elevated follistatin levels in hemodialysis (HD) patients (18,19). Thus, because heparinization during HD activates follistatin, and because we studied incident dialysis patients, the effects of recurrent heparin administration on follistatin levels in patients on maintenance HD need further consideration (19 -21).…”

Section: Discussionmentioning

confidence: 94%

Circulating Follistatin in Patients with Chronic Kidney Disease

Miyamoto

Carrero

Qureshi

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Follistatin mediates muscle growth and bone mineralization. At present, it is unknown whether circulating follistatin levels are altered in chronic kidney disease (CKD) or links to CKD risk factors and outcomes.Design, setting, participants, & measurements Plasma follistatin levels were cross-sectionally analyzed in relation to protein-energy wasting (PEW), handgrip strength (HGS), bone mineral density (BMD), and inflammatory markers in 280 CKD stage 5 patients, 32 CKD stage 4 patients, 16 CKD stage 3 patients, and 32 control subjects. In CKD stage 5 patients survival was prospectively investigated during a follow-up period of up to 5 years. ResultsThe plasma follistatin concentration was not higher in CKD stage 5 patients than in other CKD stages or controls. In CKD stage 5 patients, circulating follistatin positively correlated with age, high-sensitivity C-reactive protein (hsCRP), and IL-6; negatively correlated with HGS, serum creatinine, and BMD; and was increased in patients with PEW. In a multivariate logistic regression model, lower HGS, lower BMD, and higher hsCRP independently correlated with higher follistatin levels. In a Cox regression model, follistatin levels were not associated with all-cause mortality.Conclusions Circulating follistatin levels were neither elevated nor predicted outcome in patients with CKD. However, increased follistatin levels occurred together with increased inflammation, reduced muscle strength, and low BMD, suggesting an involvement of a mechanism including follistatin in the uremic wasting process.

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Section: Discussionmentioning

confidence: 94%

Circulating Follistatin in Patients with Chronic Kidney Disease

Miyamoto

Carrero

Qureshi

et al. 2011

Clinical Journal of the American Society of Nephrology

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“…At this time we have no explanation for this phenomenon, but our finding that this effect could not be blocked by follistatin strongly suggests that it is not an activin-like activity. Regardless, several recent studies have highlighted the fact that the concentrations of unbound, bioavailable activin are extremely low (Sakamoto et al 1996, Woodruff et al 1997, McConnell et al 1998, well below the sensitivity of the MPC-11 bioassay or other existing bioassays for activin. Therefore, to measure bioactive activin in peripheral sera would require a large improvement in the sensitivity of the assay or an approach involving extraction or purification of activin from serum.…”

Section: Discussionmentioning

confidence: 99%

A sensitive and specific in vitro bioassay for activin using a mouse plasmacytoma cell line, MPC-11

Phillips¹,

Brauman²,

Aj³

et al. 1999

Journal of Endocrinology

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A new in vitro bioassay for activin was developed using the mouse plasmacytoma cell line, MPC-11. Human recombinant (hr) activin A dose-dependently inhibited the proliferation of these cells, whereas a range of other factors, including inhibin, follistatin and transforming growth factor-1, -2 and -3 had no effect. Conditioned medium containing activin B induced an inhibition similar to hr-activin A. The inhibitory influence of activin A could be blocked by follistatin, but not by hr-inhibin A. This bioassay had a sensitivity for activin A of around 0·4 ng/ml, an ED 50 response of 3·5 ng/ml, and an intraassay coefficient of variation of <11%. It offers substantial advantages over existing in vitro activin bioassays in terms of ease of use, specificity and throughput. The utility of the MPC-11 bioassay was demonstrated in the purification of activin from amniotic fluid, where an almost identical profile of bioactive activin A was detected compared with the pituitary cell bioassay of activin. Bioactive activin could also be detected in unpurified ovine allantoic and amniotic fluids and bovine follicular fluid. Measuring activin in untreated and heat-treated human sera or seminal plasma was hampered by a non-specific inhibitory effect, so that several serum samples did not run parallel with the hr-activin A standard. This inhibitory effect by serum could not be overcome by addition of follistatin, suggesting it is not activin-like bioactivity. This new bioassay for activin demonstrates widespread applicability for monitoring of purified or partially purified samples during purification procedures, bioactivity measurements, receptor-binding studies and assays of cell culture medium.

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“…During this ten-year period, ovarian activity undergoes a significant decrease as a result of a slight but significant increase in secretion of FSH (23,24) and therefore the increased concentrations of activin A may be induced by the alterations occurring in reproductive ageing. Evidence that serum concentrations of follistatin, the binding protein for circulating activin A, do not vary with reproductive function (puberty, menstrual cycle, menopause) or hormones (FSH, estradiol) indirectly suggests that the circulating concentrations of activin A have no direct influence on reproductive function (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the possible candidates as its source -such as pituitary, adrenal cortex, liver, blood vessels or bone marrow -do not show any significant sex-related variation during the ageing processes. The increased concentrations of circulating activin A in systemic diseases and in hard or hematological malignancies (15), associated with increased concentrations of serum follistatin (27), suggest that the secretion of these proteins is most probably part of a systemic homeostatic reaction, and thus reflects a series of local paracrine/autocrine events that occur in the various organs.…”

Section: Discussionmentioning

confidence: 99%

Influence of age and sex on serum concentrations of total dimeric activin A

Loria¹,

Petraglia²,

Concari³

et al. 1998

European Journal of Endocrinology

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Several studies have shown that activin A is secreted in substantial amounts into the systemic circulation. The changes that occur during menstrual cycle and pregnancy suggest a correlation with reproductive function. At present, however, no definitive evidence has confirmed this pattern throughout adult life; moreover, neither the origin nor the physiological implications of this circulating growth factor have been clearly defined. The aim of the present study was to evaluate whether circulating concentrations of activin A change in adult men and women according to age and sex, and to examine the possible correlation with serum concentrations of FSH. Total dimeric activin A was measured using a specific two-site enzyme immunoassay in serum specimens collected from a cohort of normal individuals enrolled in an epidemiological survey. A group of men (n ¼ 106) and one of women (n ¼ 151) were subdivided into six age groups (20-30, 30-40, 40-50, 50-60, 60-70 and 70-90 years). In a small group of 8 men and 11 women, serum concentrations of activin A were evaluated twice, in specimens collected at an interval of 10 years. Serum FSH concentrations were also measured in all specimens.Serum concentrations of activin A were not significantly different in men and women and showed an age-related progressive increase between 20 and 50 years of age (P < 0.01, those aged 40-50 compared with those aged 20-30 years). After the age of 50 years, activin A concentrations remained in the same range of values in women, whereas they increased significantly in men, reaching peak values between 70 and 90 years (P < 0.01 compared with the group aged between 20 and 50 years). From the age of 50 years, activin A concentrations were significantly greater in men compared with those in women in the corresponding age groups (P < 0.001). Activin A concentrations correlated with age in men, but not in women. No significant correlation between concentrations of activin A and FSH was found in either sex. Activin A concentrations in specimens collected 10 years apart showed an increase in seven of eight men, but not in women. Finally, no significant variations of activin A concentrations were observed when fertile and postmenopausal women were compared.The present data indicate that circulating concentrations of activin A vary according to age; furthermore, men older than 50 years have greater concentrations than women. These changes, which occur irrespectively of FSH concentrations, indicate that circulating activin A is not a hormone of the reproductive axis.

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Determination of free follistatin levels in sera of normal subjects and patients with various diseases

Cited by 35 publications

References 33 publications

Circulating Follistatin in Patients with Chronic Kidney Disease

Circulating Follistatin in Patients with Chronic Kidney Disease

A sensitive and specific in vitro bioassay for activin using a mouse plasmacytoma cell line, MPC-11

Influence of age and sex on serum concentrations of total dimeric activin A

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