Mariné-Casadó Roger, Domenech-Coca Cristina, Fernández Salvador, Costa Andrea, Segarra Sergi, López-Andreo Maria José, Puiggròs Francesc, Cerón José Joaquín, Martínez-Puig Daniel, Soler Carme, Sifre Vicente, Serra Claudio Iván, Caimari Antoni
Eurecat, Centre Tecnològic de Catalunya, Technological Unit of Nutrition and Health, Reus, 43204, Spain.
Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (COS), Joint Unit, Universitat Rovira i Virgili-EURECAT, Reus, 43204, Spain.
Genes Nutr. 2024 Sep 4;19(1):19. doi: 10.1186/s12263-024-00749-2.
In a previous study, the 84-day administration of glycosaminoglycans (GAGs), with or without native collagen type II (NC), in an osteoarthritis (OA)-induced rabbit model slowed down OA progression, improved several micro- and macroscopic parameters and magnetic resonance imaging (MRI) biomarkers in cartilage, and increased hyaluronic acid levels in synovial fluid. To elucidate the potential underlying mechanisms, a transcriptomics approach was conducted using medial femoral condyle and trochlea samples.
The administration of chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), and hyaluronic acid (HA), with (CGH-NC) or without (CGH) NC, strongly modulated several genes involved in chondrocyte extracellular matrix (ECM) remodeling and homeostasis when compared to non-treated rabbits (CTR group). Notably, both treatments shared the main mechanism of action, which was related to ECM modulation through the down-regulation of genes encoding proteolytic enzymes, such as ADAM metallopeptidase with thrombospondin type 1 motif, 9 (Adamts9), and the overexpression of genes with a relevant role in the synthesis of ECM components, such as aggrecan (Acan) in both CGH-NC and CGH groups, and fibronectin 1 (Fn1) and collagen type II, alpha 1 (Col2A1) in the CGH group. Furthermore, there was a significant modulation at the gene expression level of the mTOR signaling pathway, which is associated with the regulation of the synthesis of ECM proteolytic enzymes, only in CGH-NC-supplemented rabbits. This modulation could account for the better outcomes concerning the microscopic and macroscopic evaluations reported in these animals.
In conclusion, the expression of key genes involved in chondrocyte ECM remodeling and homeostasis was significantly modulated in rabbits in response to both CGH and CGH-NC treatments, which would partly explain the mechanisms by which these therapies exert beneficial effects against OA.
在先前的一项研究中，在骨关节炎（OA）诱导的兔模型中，连续84天给予糖胺聚糖（GAGs），无论有无天然II型胶原蛋白（NC），均减缓了OA进展，改善了软骨中几个微观和宏观参数以及磁共振成像（MRI）生物标志物，并提高了滑液中的透明质酸水平。为了阐明潜在的机制，使用股骨内侧髁和滑车样本进行了转录组学研究。
与未治疗的兔子（CTR组）相比，给予硫酸软骨素（CS）、盐酸氨基葡萄糖（GlHCl）和透明质酸（HA），无论有无NC（CGH-NC或CGH），均强烈调节了几个参与软骨细胞细胞外基质（ECM）重塑和稳态的基因。值得注意的是，两种治疗方法具有共同的主要作用机制，即通过下调编码蛋白水解酶的基因（如含血小板反应蛋白基序的ADAM金属蛋白酶9（Adamts9））来调节ECM，并上调在ECM成分合成中起相关作用的基因，如CGH-NC组和CGH组中的聚集蛋白聚糖（Acan），以及CGH组中的纤连蛋白1（Fn1）和II型胶原蛋白α1（Col2A1）。此外，仅在补充CGH-NC的兔子中，mTOR信号通路的基因表达水平有显著调节，该通路与ECM蛋白水解酶合成的调节有关。这种调节可以解释这些动物在微观和宏观评估中取得更好结果的原因。
总之，CGH和CGH-NC治疗均显著调节了兔软骨细胞ECM重塑和稳态相关关键基因的表达，这将部分解释这些疗法对OA产生有益作用的机制。
