Tripathi Gyanoday, Bhombe Komal, Chatterjee Deep Rohan, Das Rudradip, Goyal Divya, Shard Amit, Kumar Hemant
National Institute of Pharmaceutical Education and Research Ahmedabad, Gandhinagar, India.
Eur Spine J. 2025 Jun 6. doi: 10.1007/s00586-025-09014-5.
Intervertebral disc degeneration (IVDD) is a major contributor to lower back pain and disability, driven by alterations in extracellular matrix (ECM) remodelling and inflammation following chondroptosis. While the relationship between IVDD and ECM biochemical changes is well-established, the specific role of pyruvate kinase M2 (PKM2) in this process remains unexplored. This study aimed to investigate the involvement of PKM2 in a Chondroitinase ABC (ChABC)-induced model of IVDD.
We administered three different dosages of ChABC (0.0001U, 0.00025U, and 0.0005U) in the coccygeal disc. Subsequently, the model was validated through behavioural tests (tail flick and von Frey). Additionally, a comprehensive morphological evaluation of the disc was assessed using H&E, MT, and SO-FG staining. Also, various IHC markers like Collagen-I, II, Aggrecan, and SOX-9 expressions were analyzed.
Administration of a 0.00025U dose of ChABC at day 28 led to a significant upregulation of PKM2, TSK, IL-1β, and cellular hypertrophy, all hallmarks of IVDD. The onset of IVDD was associated with a decrease in collagen-II, Aggrecan, and markers of chondrogenesis, contributing to increased pain, inflammation, and tissue disorganization. Notably, selective inhibition of PKM2 using IMID-284 resulted in reduced pain and inflammation, alongside a protective effect on cartilage, suggesting that PKM2 plays a pivotal role in IVDD pathophysiology.
These findings indicate that PKM2 inhibition may represent a promising therapeutic strategy for mitigating the biochemical and structural changes underlying disc degeneration. Overall, the study provides new insights into how PKM2 inhibition could arrest the progression of IVDD, pain, and inflammation.
椎间盘退变（IVDD）是下腰痛和残疾的主要原因，由软骨细胞凋亡后细胞外基质（ECM）重塑和炎症改变所驱动。虽然IVDD与ECM生化变化之间的关系已得到充分证实，但丙酮酸激酶M2（PKM2）在此过程中的具体作用仍未得到探索。本研究旨在调查PKM2在软骨素酶ABC（ChABC）诱导的IVDD模型中的参与情况。
我们在尾椎椎间盘中给予三种不同剂量的ChABC（0.0001U、0.00025U和0.0005U）。随后，通过行为测试（甩尾和von Frey）对模型进行验证。此外，使用苏木精和伊红（H&E）、甲苯胺蓝（MT）和番红固绿（SO-FG）染色对椎间盘进行全面的形态学评估。同时，分析了各种免疫组化标志物，如I型、II型胶原蛋白、聚集蛋白聚糖和SOX-9的表达。
在第28天给予0.00025U剂量的ChABC导致PKM2、TSK、白细胞介素-1β（IL-1β）显著上调以及细胞肥大，这些都是IVDD的特征。IVDD的发生与II型胶原蛋白、聚集蛋白聚糖和软骨形成标志物的减少有关，导致疼痛、炎症和组织紊乱增加。值得注意的是，使用IMID-284选择性抑制PKM2可减轻疼痛和炎症，并对软骨具有保护作用，这表明PKM2在IVDD病理生理学中起关键作用。
这些发现表明，抑制PKM2可能是减轻椎间盘退变潜在生化和结构变化的一种有前景的治疗策略。总体而言，该研究为PKM2抑制如何阻止IVDD、疼痛和炎症的进展提供了新的见解。
