Biological activity and in vivo half-life of pro-activin A in male rats. (15th February 2016)

• Record Type: Journal Article
• Authors: Johnson, Katharine E.; Makanji, Yogeshwar; Temple-Smith, Peter; Kelly, Emily K.; Barton, Peter A.; Al-Musawi, Sara L.; Mueller, Thomas D.; Walton, Kelly L.; Harrison, Craig A.
• Is Part Of: Molecular and cellular endocrinology. Volume 422(2016)
• Page Start: 84
• Page End: 92
• Publication Date: 2016-02-15
• Subjects: Activin -- Transforming growth factor-β superfamily -- Prodomain -- Half-life; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.12.007
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Mature TGF-β proteins are used in vivo to promote bone growth, combat obesity, reverse fibrosis and pulmonary arterial hypertension, and as potential rejuvenation factors. However, the serum half-life of this family of growth factors is short (∼5 min), limiting their therapeutic potential. Because TGF-β proteins are normally secreted from cells with their prodomains attached, we considered whether these molecules could extend the in vivo half-life and activity of their respective growth factors. Using activin A as a model ligand, we initially modified the cleavage site between the pro- and mature domains to ensure complete processing of the activin A precursor. Co-immunoprecipitation studies confirmed mature activin A is secreted from cells in a non-covalent complex with its prodomain, however, the affinity of this interaction is not sufficient to suppress activin A in vitro biological activity. The plasma clearance profiles of purified pro- and mature activin A were determined over a 4 h period in adult male rats. Both activin forms demonstrated a two-phase decay, with the half-life of pro-activin A (t1/2 fast = 12.5 min, slow = 31.0 min) being greater than that of mature activin A (t1/2 fast = 5.5 min, slow = 20.3 min). Both pro- and mature activin A induced significant increases in serum follicle stimulating hormone levels after 4 h, but no differences were observed in the relative in vivo bioactivities of the two activin isoforms. Increased serum half-life of activin A in the presence of its prodomain identifies a new means to increase the therapeutic effectiveness of TGF-β proteins. Highlights: Activin A is secreted from the cell in a non-covalent complex with its prodomain. The presence of the prodomain does not limit the in vitro bioactivity of activin A. In vivo half-life of activin A is increased when bound to its prodomain.