Projects per year
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.
Original language | English |
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Pages (from-to) | 84 - 92 |
Number of pages | 9 |
Journal | Molecular and Cellular Endocrinology |
Volume | 422 |
DOIs | |
Publication status | Published - 15 Feb 2016 |
Projects
- 1 Finished
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Physiological consequences of the loss of inhibin activity
Harrison, C. (Primary Chief Investigator (PCI)), Gaddy, D. (Chief Investigator (CI)), Gillespie, M. (Chief Investigator (CI)), Gregorevic, P. (Chief Investigator (CI)) & Robertson, D. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/17
Project: Research