A Novel Interplay Between Irisin and PTH: From Basic Studies to Clinical Evidence in Hyperparathyroidism

Context: Irisin is a hormonelike molecule that is cleaved and secreted by an unknown protease from fibronectin type III domain-containing protein 5 (FNDC5). It ameliorates bone status and muscle atrophy and influences energy homeostasis. PTH exerts several metabolic effects that may interact with the effects of irisin. Objectives: To test the hypothesis that irisin and PTH mutually affect their biological action, we evaluated FNDC5 mRNA and protein expression in myotubes treated with PTH (1-34) and parathyroid hormone receptor (PTH-r) mRNA expression in osteoblasts treated with r-irisin. To confirm the in vivo impact of PTH on irisin, we compared irisin serum concentrations in postmenopausal women with primary hyperparathyroidism (PHPT) and control subjects. Design and Intervention: C2C12 myotubes were treated with short-term and continuous 10(-10) M teriparatide and MC3T3-E1 osteoblasts with 100 ng/mL r-irisin for 8 hours. In a cross-sectional open-label trial, we enrolled 26 postmenopausal women with PHPT and 31 age-/body mass index (BMI)-matched control subjects without impairment of calcium/phosphate metabolism. Results: Teriparatide treatment on myotubes significantly downregulated FNDC5 expression by acting through its own receptor, which in turn activated Erk11/2 phosphorylation. r-Irisin led to a 50% downregulation of PTH-r mRNA expression compared with untreated cells (P < 0.001). Irisin was significantly lower in the PHPT group than in age-/BMI-matched controls (4.5 +/- 1.1 vs 12 +/- 5.2 mu g/mL; P < 0.001). No significant correlation between irisin and bone mineral density or PTH was recorded in the PHPT group. Conclusion: Preclinical findings suggest the existence of an interplay between PTH and irisin metabolism that seems to be confirmed by the significant reduction of irisin concentration in postmenopausal women with PHPT.