Figure 1.

Potential mechanisms signaling pathways for the actions of irisin in musculoskeletal. During exercise, the elevated Ca²⁺ in muscle cytoplasm-induced activation of the AMPK–PGC-1α–FNDC5 axis is the main pathway for irisin synthesis. In addition, irisin, in turn, can stimulate muscle growth and myoblast differentiation via ERK1/2–IGF-1/MSTN and IL-6 signaling pathways, respectively. Multiple pathways mediated exercise-induced irisin and r-irisin–activated osteoblast differentiation and mineralization, e.g., p38/ERK1/2, Akt-β-catenin, and Wnt-β-catenin–mediated activation of ALP/OCN/Col I pathways. In osteoclast, irisin induced its proliferation through activating the p38/JNK pathway. In addition, irisin also inhibited the NF-κB and NFATc1 levels in the nucleus, thus inhibiting the expression of osteoclast differentiation marker genes. As for osteocytes, irisin inhibited osteocyte apoptosis by inhibiting caspase-9 and caspase-3 expression, which probably through activating p38/ERK1/2. Furthermore, moderate exercise-activated irisin or r-irisin could alleviate OA by maintaining ECM stabilization and reducing inflammatory response through p38/JNK-Akt and PI3K/Akt/NF-κB signaling pathway, respectively.