Modulation of PTH Affects the Action of Irisin on Bone in a Rat Model of CKD-MBD

Background: Despite use of PTH-lowering therapies, fractures in CKD patients have not decreased, indicating other factors may modulate the effect of PTH on bone. One such factor is irisin, a myokine produced by skeletal muscle from its precursor, Fndc5. This study sought to determine the effect of irisin on bone under high and low PTH in CKD-MBD in vivo. Methods: 22 wk male Cy/+ rats, which model progressive CKD-MBD, were divided into 4 groups. Half received normal drinking water and half 2% calcium gluconate water to continuously suppress PTH, then at 27 wks, recombinant irisin injections (i.p. 3x/wk, 30 µg/kg) or no treatment were administered for 5 wks. Plasma PTH and serum procollagen type I N-terminal propeptide (PINP) were assessed via ELISA. Tb bone formation rate (BFR) was determined by dynamic histomorphometry of the proximal tibia. Muscle Fndc5 mRNA was assessed via qPCR. Data were analyzed by one-way ANOVA or simple linear regression. Results: There was no difference in BUN or creatinine b/w groups. 2% calcium suppressed PTH with and without irisin (1a). Neither 2% calcium nor irisin alone affected PINP, a marker of bone turnover, but the combination decreased PINP by half (p<0.0001) compared to CKD (1b). Preliminary histomorphometry (n=5) indicates a trend toward an increase in mineral apposition rate (MAR) and BFR in the irisin group. However, this effect is blunted when also treated with calcium (1c,d). There was no difference in Fndc5 mRNA b/w groups in the soleus or EDL, but there was a significant negative correlation between Fndc5 mRNA and PTH in both the soleus (p<0.0001, r2=0.414) and EDL (p=0.02, r2=0.116) (2a,b). Conclusion: These data indicate that continuously high PTH may blunt the effect of irisin on bone turnover in a rat model of CKD-MBD. Ongoing studies will examine this interaction via µCT and mechanical testing and a potential mechanism in vitro. Funding: NIDDK Support - NIDDK Support, NIDDK Support