Gao Yong, Wang Ke, Shi Chao, Gao Yang, Kong De-Qian
Department of Orthopaedic Surgery, The Second Affiliated Hospital of Shandong First Medical University, No. 366, Taishan Street, Taishan District, Tai'an City, Shandong Province, China.
Rehabilitation Department, Taishan Vocational College of Nursing, Tai'an City, Shandong Province, China.
J Orthop Surg Res. 2025 May 3;20(1):441. doi: 10.1186/s13018-025-05804-1.
Osteoarthritis (OA) is an age-related progressive degenerative disorder characterized by cartilage extracellular matrix degradation and inflammation. In this study, we explored the function and mechanism of action of obacunone (OB) in inhibiting OA progression.
The degradation of articular cartilage and its severity were examined using Safranin O-fast green and hematoxylin and eosin (HE) staining. Chondrocyte survival was evaluated using a cell counting kit-8 assay. In addition, qRT-PCR, western blot analysis, immunohistochemical staining, and enzyme-linked immunosorbent assay were performed to evaluate the effects of OB on cartilage injury.
OB mitigated cartilage lesions in rats with anterior cruciate ligament transaction-induced OA. The protein expression of collagen II was increased and the protein expression of ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS-5), matrix metalloproteinase (MMP)-13, and RUNX family transcription factor 2 (RUNX2) was reduced in the articular cartilage of OB-treated rats. Moreover, OB exhibited anti-inflammatory activities by reducing the serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, and IL-18. In IL-1β-stimulated primary chondrocytes, OB dose-dependently elevated the expression of collagen II, and decreased the expression of ADAMTS-5, MMP-13, RUNX2 and inflammatory cytokines. Histone deacetylase 1 (HDAC1) was identified as a predicted OB target. OB inhibited HDAC1 expression to limit the activation of p38MAPK signaling. The transfection of chondrocytes with HDAC1 or p38MAPK overexpression plasmids reversed the chondroprotective effects of OB.
OB mitigated OA progression by binding to HDAC1 and inhibiting p38MAPK signaling, indicating that OB may be a promising drug for the treatment of OA.
骨关节炎（OA）是一种与年龄相关的进行性退行性疾病，其特征为软骨细胞外基质降解和炎症。在本研究中，我们探讨了奥巴库酮（OB）抑制OA进展的作用及作用机制。
使用番红O-固绿染色和苏木精-伊红（HE）染色检查关节软骨的降解情况及其严重程度。使用细胞计数试剂盒-8检测法评估软骨细胞存活率。此外，进行qRT-PCR、蛋白质印迹分析、免疫组织化学染色和酶联免疫吸附测定，以评估OB对软骨损伤的影响。
OB减轻了前交叉韧带横断诱导的OA大鼠的软骨损伤。在OB处理的大鼠关节软骨中，Ⅱ型胶原蛋白的蛋白表达增加，而含血小板反应蛋白基序的解聚素样金属蛋白酶5（ADAMTS-5）、基质金属蛋白酶（MMP）-13和RUNX家族转录因子2（RUNX2）的蛋白表达降低。此外，OB通过降低血清白细胞介素（IL）-6（白细胞介素6）、肿瘤坏死因子（TNF）-α、IL-1β和IL-18的水平表现出抗炎活性。在IL-1β刺激的原代软骨细胞中，OB剂量依赖性地提高Ⅱ型胶原蛋白的表达，并降低ADAMTS-5、MMP-13、RUNX2和炎性细胞因子的表达。组蛋白去乙酰化酶1（HDAC1）被确定为预测的OB靶点。OB抑制HDAC1表达以限制p38MAPK信号通路的激活。用HDAC1或p38MAPK过表达质粒转染软骨细胞可逆转OB的软骨保护作用。
OB通过与HDAC1结合并抑制p38MAPK信号通路减轻OA进展，表明OB可能是一种有前景的OA治疗药物。
