Shih Yu-Ru V, Tao Huchen, Gilpin Anna, Lee Yuan-Wen, Perikamana Sajeeshkumar Madhurakkat, Varghese Shyni
Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27710, USA.
Osteoarthritis Cartilage. 2025 Mar;33(3):341-350. doi: 10.1016/j.joca.2024.10.018. Epub 2024 Nov 29.
We test whether the specialized pro-resolving molecule Maresin 1 (MaR1) attenuates nociceptive behaviors in mice with osteoarthritis-like pain.
Osteoarthritis (OA)-like pain behavior was induced by intra-articular injection of monosodium iodoacetate (MIA) and treated with MaR1 (N=6) or vehicle (N=5) by intraperitoneal injection 8 weeks after injury. Mice without MIA injection were used as control (N=6). Nociceptive behaviors were examined by von Frey and dynamic weight bearing measurements. Calcitonin gene-related peptide (CGRP) expression and activated macrophages in the dorsal root ganglion (DRG) were examined by immunofluorescence staining. The inflammatory profile in circulation was assessed by cytokine array. Calcium imaging was performed to assess the in vitro functional response of DRG neurons from animals with OA-like pain behavior to MaR1 with or without RAR Related Orphan Receptor A (RORA) inverse agonist SR3335.
MaR1 attenuated knee pain behavior in treated mice (N=6) compared to non-treated mice (N=5) as shown by increased paw withdrawal threshold with a mean difference of 112.2% (95% CI [49.79, 174.6], p=0.0784) at 4 h and 150.9% (95% CI [104.2, 197.5], p=0.0001) at 4 days post-MaR1 treatment, and increased weight bearing with a mean difference of 20.08% (95% CI [2.798, 37.37], p=0.0277) at 1 day post-MaR1 treatment. CGRP expression and activated macrophages were decreased in the DRG, and inflammatory cytokine levels in the circulation were attenuated. Calcium imaging showed MaR1 reduced the functional response of DRG neurons through RORA.
Our results show that MaR1 reduces OA-like pain behavior in mice and could be a potential treatment for OA pain.
我们测试了特异性促消退分子maresin 1（MaR1）是否能减轻患有骨关节炎样疼痛的小鼠的伤害性反应行为。
通过关节内注射碘乙酸钠（MIA）诱导骨关节炎（OA）样疼痛行为，并在损伤8周后通过腹腔注射MaR1（N = 6）或赋形剂（N = 5）进行治疗。未注射MIA的小鼠用作对照（N = 6）。通过von Frey和动态负重测量来检查伤害性反应行为。通过免疫荧光染色检查背根神经节（DRG）中降钙素基因相关肽（CGRP）的表达和活化的巨噬细胞。通过细胞因子阵列评估循环中的炎症谱。进行钙成像以评估具有OA样疼痛行为的动物的DRG神经元对有或没有RAR相关孤儿受体A（RORA）反向激动剂SR3335的MaR1的体外功能反应。
与未治疗的小鼠（N = 5）相比，MaR1减轻了治疗小鼠（N = 6）的膝关节疼痛行为，如在MaR1治疗后4小时，爪退缩阈值增加，平均差异为112.2%（95%CI[49.79,174.6]，p = 0.0784），在4天时增加150.9%（95%CI[104.2,197.5]，p = 0.0001），并且在MaR1治疗后1天负重增加，平均差异为20.08%（95%CI[2.798,37.37]，p = 0.0277）。DRG中CGRP的表达和活化的巨噬细胞减少，循环中的炎性细胞因子水平降低。钙成像显示MaR1通过RORA降低了DRG神经元的功能反应。
我们的结果表明，MaR1可减轻小鼠的OA样疼痛行为，可能是OA疼痛的一种潜在治疗方法。
