羟基柠檬酸通过改变软骨细胞的代谢级联来重建受损的关节软骨。

Osteoarthritis and cartilage open Pub Date : 2024-12-24 DOI:10.1016/j.ocarto.2024.100564

Yoshiyuki Mizushina , Liping Sun , Megumi Nishio , Sanae Nagata , Takeshi Kamakura , Masayuki Fukuda , Kousuke Tanaka , Junya Toguchida , Yonghui Jin

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引用次数: 0

摘要

目的：骨关节炎是一种退行性关节疾病，由于软骨再生能力有限，需要创新疗法。由于间充质干细胞（MSCs）为成软骨细胞提供了细胞来源，我们假设能够增强MSCs转化生长因子- β (TGFβ)的成软骨潜能的化学物质在体外可能同样促进关节软骨的成软骨。设计：利用人诱导多能干细胞衍生的间充质干细胞，研究了增强TGFβ信号通路促进软骨形成的化合物。研究人员在体外探索了所鉴定化合物的作用机制，并利用小鼠运动性骨关节炎模型在体内验证了其治疗效果。结果：羟基柠檬酸（HCA）为先导化合物。在体外，HCA通过抑制ATP柠檬酸裂解酶，诱导柠檬酸和α-酮戊二酸（α-KG），同时降低胞质乙酰辅酶A (Ac-CoA)，有效促进软骨形成。α-KG的诱导促进了胶原脯氨酸-4-羟化酶的活性，促进了羟脯氨酸的产生和基质的形成。Ac-CoA的减少通过降低β-catenin的乙酰化，减弱了β-catenin对线粒体活性的抑制作用。在体内，口服HCA在小鼠关节组织中积累，组织学检查显示损伤区新合成的软骨组织。对关节组织提取物的分析显示，Ac-CoA下调，柠檬酸盐和α-KG上调，并伴有合成代谢生物标志物的全身增加。结论：HCA通过增强软骨分化显示了作为骨关节炎治疗的希望。其调节关键代谢途径和促进软骨修复的能力表明其具有潜在的临床转化潜力，解决了骨关节炎治疗的关键需求。

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Hydroxycitric acid reconstructs damaged articular cartilages by modifying the metabolic cascade in chondrogenic cells

Objective

Osteoarthritis, a degenerative joint disease, requires innovative therapies due to the limited ability of cartilage to regenerate. Since mesenchymal stem cells (MSCs) provide a cell source for chondrogenic cells, we hypothesize that chemicals capable of enhancing the chondrogenic potential of MSCs with transforming growth factor-beta (TGFβ) in vitro may similarly promote chondrogenesis in articular cartilage in vivo.

Design

Chemical compounds that enhance the TGFβ signaling for chondrogenesis were investigated utilizing mesenchymal stem cells derived from human induced pluripotent stem cells. The mechanisms of action underlying the identified compound were explored in vitro, and its therapeutic effects were validated in vivo using a mouse model of exercise-induced osteoarthritis.

Results

Hydroxycitric acid (HCA) emerged as the lead compound. In vitro, HCA effectively enhanced chondrogenesis by inhibiting ATP citrate lyase, inducing citrate and alpha-ketoglutarate (α-KG), while reducing cytosolic acetyl coenzyme A (Ac-CoA). This induction of α-KG promoted collagen prolyl-4-hydroxylase activity, boosting hydroxyproline production and matrix formation. The reduction of Ac-CoA attenuated the inhibitory effect of β-catenin on mitochondrial activity by diminishing its acetylation. In vivo, orally administered HCA accumulated in joint tissues of mice and histological examination demonstrated newly synthesized cartilage tissues in damaged area. Analysis of joint tissue extracts revealed a downregulation of Ac-CoA and an upregulation of citrate and α-KG, accompanied by a systemic increase in an anabolic biomarker.

Conclusions

HCA demonstrates promise as an osteoarthritis therapy by enhancing chondrogenic differentiation. Its ability to modulate crucial metabolic pathways and facilitate cartilage repair suggests potential for clinical translation, addressing a critical need in the treatment of osteoarthritis.

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来源期刊

Osteoarthritis and cartilage open Orthopedics, Sports Medicine and Rehabilitation

CiteScore

3.30

自引率

0.00%

发文量