Irisin inhibits osteocyte apoptosis by activating the Erk signaling pathway in vitro and attenuates ALCT-induced osteoarthritis in mice

Moderate exercise can alleviate symptoms of osteoarthritis (OA) such as pain, stiffness, and joint deformities that are associated with progressive cartilaginous degeneration, osteophyte formation, subchondral bone changes, and synovial inflammation. Irisin is an exercise-related myokine that reportedly plays a crucial role in bone remodeling. However, its role in OA remains unknown. This study aimed to determine whether irisin can attenuate OA progression and the mechanism of its therapeutic effect. Three-month-old male C57BL/6J mice were randomized to groups that underwent sham operation, and anterior cruciate ligament transection (ACLT) intraperitoneally injected with vehicle or irisin in vivo. Apoptosis was induced by stretching murine osteocyte-like MLO-Y4 cells in vitro. Irisin reduced wear, maintained the proportion of hyaline cartilage, a more complete cartilage structure, and lower Osteoarthritis Research Society International (OARSI) scores at 4 weeks after ACLT. Irisin reduced the expression of matrix metalloproteinase (MMP)-13 in cartilage and caspase 3 in the subchondral bone. Irisin exerted rescue effects in microstructural parameters of subchondral trabecular bone including bone volume fraction (BV/TV), trabecular number (Tb.N), connection density (Conn. D), and the structure model index (SMI) compared with ACLT-vehicle group. Bone histomorphometry showed that irisin increased subchondral bone remodeling. The decreasing ratio (%) of the eroded surface (ES/BS) was reversed by irisin in the ACLT+vehicle group. Staining with tartrate-resistant acid phosphatase showed a decreased number of osteoclasts. Irisin significantly increased the proliferation of osteocytes, protected them from apoptosis, and maintained cellular activity by regulating the expression of Bax, Bcl-2, and osteoprotegerin/receptor activator of nuclear factor (NF)-kB-ligand (OPG/Rankl). Irisin activated serine/threonine-selective protein kinases (Erk) and p38 signaling, and its anti-apoptosis function depended on the Erk signaling pathway. Irisin attenuated OA progression by decreasing osteocyte apoptosis and improving the microarchitecture of subchondral bone. Activation of the Erk pathway by irisin plays an important role in reducing osteocyte apoptosis in vitro.