The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4⁺ T cells in peripheral blood and spleen. Deletion of CD4⁺ T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4⁺ T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint–liver axis mediated by matrikine-activated CD4⁺ T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease.

膝关节长期以来被认为是一个封闭的系统。关节疾病对远处器官的病理影响尚未被研究。在此，我们的临床数据表明，与健康对照相比，外伤后关节损伤加上关节出血（关节积血）表现出更差的肝功能。在小鼠模型中，关节积血会引起软骨变性和远程肝损伤。接下来，我们发现关节积血会导致外周血和脾脏中CD4 ⁺ T细胞比例上调和向Th17细胞分化。 CD4 ⁺ T 细胞的缺失可以逆转关节积血引起的肝损伤。关节积血引起的软骨基质退化会上调血清学 II 型胶原 (COL II)，从而激活 CD4 ⁺ T 细胞。全身应用 COL II 抗体可阻断激活。此外，大量 RNAseq 和单细胞 qPCR 分析表明，软骨 Akt 通路受到血液处理的抑制。在小鼠和猪模型中，关节内应用 Akt 激活剂可阻止软骨退化，从而防止肝损伤。综上所述，我们的研究揭示了由苦参碱激活的 CD4 ⁺ T 细胞介导的病理性关节-肝轴，它刷新了器官串扰轴，并为关节积血相关疾病提供了新的治疗靶点。