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

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.

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.

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.

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 µg/mL; P < 0.001). No significant correlation between irisin and bone mineral density or PTH was recorded in the PHPT group.

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.