GH replacement therapy in adults stimulates Fibroblast Activation Protein-α activity

Background Growth hormone (GH) potently stimulates collagen turnover which underlies its anabolic effects on bone in children, whereas it may promote fibrosis in adults. Fibroblast activation protein-α (FAPα) is a serine protease which substrates include collagen and fibroblast growth factor 21 (FGF21). FAPα levels are reversibly elevated in active acromegaly. Aim To measure circulating FAPα activity and levels, as well as FAPα substrates, in adult patients with GH-deficiency (GHD) before and after GH replacement therapy. Methods FAPα activity and levels were analyzed in serum samples from two groups of GHD patients before and after 3-6 months GH replacement therapy as compared to non-GHD hypopituitary patients and a healthy reference group. Furthermore, collagen turnover biomarkers (PINP, PIIINP, CTx) and intact FGF21 were analyzed. Results FAPα activity (RFU/min) significantly increased after GH replacement in both GHD groups [290.6±47.8 (before) vs. 428.5±66.4 (after) p<0.05; 291.0±37.4 (before) vs. 403.0±52.9 (after); p<0.05]. Likewise, FAPα levels significantly increased by 40% after GH replacement in both groups (p<0.01) and correlated closely with FAPα activity. PINP, PIIINP and CTx significantly increased after 3 months of GH replacement. Intact FGF21 remained unchanged. Conclusions 1) Our study documents for the first time that GH stimulates FAPα activity in vivo in human subjects. 2) The concomitant increase in collagen turnover and the lack of change in intact FGF21 suggest that GH-driven FAPα activity predominantly involves collagen breakdown, and 3) FAPα is a novel biomarker of GH/IGF-I activity and may be causally linked to GH-induced fibrosis.