Wang Zhengming, Huang Junyan, Feng Yuanyuan, Li Zhengyan, Ge Haiya, Wang Rui, Gu Yong, Xiong Yizhe, Chen Bo, Zhang Mingcai, Wang Xiang, Shi Ying, Shen Zhibi, Zhan Hongsheng, Du Guoqing
Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China.
J Cell Mol Med. 2025 May;29(9):e70577. doi: 10.1111/jcmm.70577.
Knee osteoarthritis (KOA), a degenerative joint disease driven by biomechanical instability, involves cartilage degradation, muscle dysfunction, and MLK3/P38 MAPK pathway activation. Histone deacetylase 4 (HDAC4), a regulator of chondrocyte and muscle homeostasis, interacts with this pathway during disease progression. While Hyriopsis Bioactive Polysaccharide-Anodonta (HBP-A) exhibits P38 MAPK inhibitory properties in vitro, its in vivo therapeutic effects on musculoskeletal tissues remain uncharacterised. A destabilisation of the medial meniscus (DMM) mouse model was established to investigate HBP-A's therapeutic potential. Animals were randomly divided into sham-operated, DMM-induced, and HBP-A-treated groups. Following surgical induction, HBP-A (0.26 g/kg) was administered daily via oral gavage for 4 weeks. Comprehensive assessments included behavioural tests for pain sensitivity, micro-CT scanning, histological evaluation, and transmission electron microscope. Molecular mechanisms were investigated via immunohistochemical or immunofluorescence staining of MLK3, P38 MAPK, Caspase-3, and HDAC4, complemented by RT-qPCR analysis of myokine expression. HBP-A treatment significantly alleviated pain sensitivity compared to the DMM group. Structural evaluations revealed preserved subchondral bone integrity and attenuated cartilage degeneration, with histological scoring confirming reduced pathological changes. Quadriceps exhibited mitigated atrophy and restored ultrastructural organisation. Molecular profiling demonstrated suppressed MLK3/P38 MAPK pathway activation, diminished apoptotic activity, and elevated HDAC4 expression in both cartilage and quadriceps. HBP-A additionally normalised dysregulated expression of muscle-derived osteogenic factors linked to bone-cartilage crosstalk. These findings establish HBP-A as a dual-target therapeutic agent for KOA, concurrently mitigating cartilage and muscle degeneration through MLK3/P38 MAPK/HDAC4 axis modulation.
膝骨关节炎（KOA）是一种由生物力学不稳定驱动的退行性关节疾病，涉及软骨降解、肌肉功能障碍和MLK3/P38丝裂原活化蛋白激酶（MAPK）通路激活。组蛋白去乙酰化酶4（HDAC4）是软骨细胞和肌肉稳态的调节因子，在疾病进展过程中与该通路相互作用。虽然三角帆蚌生物活性多糖（HBP-A）在体外具有P38 MAPK抑制特性，但其对肌肉骨骼组织的体内治疗效果仍未明确。建立内侧半月板不稳定（DMM）小鼠模型以研究HBP-A的治疗潜力。动物被随机分为假手术组、DMM诱导组和HBP-A治疗组。手术诱导后，通过口服灌胃每天给予HBP-A（0.26 g/kg），持续4周。综合评估包括疼痛敏感性行为测试、显微计算机断层扫描（micro-CT）、组织学评估和透射电子显微镜检查。通过对MLK3、P38 MAPK、半胱天冬酶-3（Caspase-3）和HDAC4进行免疫组织化学或免疫荧光染色研究分子机制，并通过对肌动蛋白的逆转录定量聚合酶链反应（RT-qPCR）分析进行补充。与DMM组相比，HBP-A治疗显著减轻了疼痛敏感性。结构评估显示软骨下骨完整性得以保留，软骨退变减轻，组织学评分证实病理变化减少。股四头肌萎缩减轻，超微结构组织得以恢复。分子分析表明，软骨和股四头肌中MLK3/P38 MAPK通路激活受到抑制，凋亡活性降低，HDAC4表达升高。HBP-A还使与骨-软骨相互作用相关的肌肉源性成骨因子的失调表达恢复正常。这些发现表明HBP-A是一种用于KOA的双靶点治疗药物，通过调节MLK3/P38 MAPK/HDAC4轴同时减轻软骨和肌肉退变。
