Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Bone. 2020 Dec;141:115573. doi: 10.1016/j.bone.2020.115573. Epub 2020 Aug 5.
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.
适度运动可以缓解骨关节炎（OA）的症状，如疼痛、僵硬和关节畸形，这些症状与进行性软骨退化、骨赘形成、软骨下骨变化和滑膜炎有关。鸢尾素是一种与运动相关的肌因子，据报道它在骨重塑中起着关键作用。然而，它在 OA 中的作用尚不清楚。本研究旨在确定鸢尾素是否能减轻 OA 的进展及其治疗效果的机制。将 3 个月大的雄性 C57BL/6J 小鼠随机分为假手术组和前交叉韧带切断术（ACLT）组，通过腹腔内注射载体或鸢尾素。体外拉伸鼠成骨细胞样 MLO-Y4 细胞诱导细胞凋亡。鸢尾素减少了 ACLT 后 4 周时的磨损，保持了透明软骨的比例，更完整的软骨结构和较低的骨关节炎研究协会国际（OARSI）评分。鸢尾素降低了软骨中基质金属蛋白酶（MMP）-13 和软骨下骨中半胱氨酸天冬氨酸蛋白酶 3 的表达。与 ACLT-载体组相比，鸢尾素对软骨下骨小梁的微观结构参数（包括骨体积分数（BV/TV）、骨小梁数（Tb.N）、连接密度（Conn.D）和结构模型指数（SMI））有恢复作用。骨组织形态计量学显示，鸢尾素增加了软骨下骨重塑。与 ACLT+载体组相比，鸢尾素逆转了侵蚀表面（ES/BS）减少的比例（%）。抗酒石酸酸性磷酸酶染色显示破骨细胞数量减少。鸢尾素通过调节 Bax、Bcl-2 和骨保护素/核因子（NF）-kB 配体（OPG/Rankl）受体激活剂的表达，显著增加成骨细胞的增殖，保护其免于凋亡并维持细胞活性。鸢尾素激活丝氨酸/苏氨酸选择性蛋白激酶（Erk）和 p38 信号通路，其抗凋亡功能依赖于 Erk 信号通路。鸢尾素通过减少成骨细胞凋亡和改善软骨下骨的微观结构来减轻 OA 的进展。鸢尾素通过激活 Erk 通路在体外减少成骨细胞凋亡中起重要作用。
