Subchondral injection of human umbilical cord mesenchymal stem cells ameliorates knee osteoarthritis by inhibiting osteoblast apoptosis and TGF-beta activity.

IF 7.1 2区医学 Q1 CELL & TISSUE ENGINEERING

Stem Cell Research & Therapy Pub Date : 2025-05-09 DOI:10.1186/s13287-025-04366-7

Congzi Wu, HuiHui Xu, Zhen Wu, Haipeng Huang, Qinwen Ge, Jianbo Xu, Jiali Chen, Pinger Wang, Wenhua Yuan, Hongting Jin, Peijian Tong

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引用次数: 0

Abstract

Background: Osteoarthritis (OA) is a common degenerative disease caused by multiple pathological mechanisms wherein subchondral bone malfunction plays a substantial role. Recently, subchondral (SC) injection of orthobiologics has been attracting growing interest albeit the mainstream delivery method of mesenchymal stem cells (MSCs) is through intra-articular (IA). This study investigates the effect of SC injection of human umbilical cord mesenchymal stem cells (UCMSCs) on OA and its possible therapeutic mechanism compared to IA injection.

Methods: Male Sprague-Dawley rats with anterior cruciate ligament transection (ACLT) received saline or UCMSC injections via SC or IA. Consecutive injections once a week for three weeks and withdrawal for another four weeks, followed by Radiographical scanning, histopathological, immunohistochemical, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining. Cell counting Kit-8 (CCK-8) assay, alkaline phosphatase (ALP), alizarin red staining (ARS), TUNEL, flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed in TNFα-induced MC3T3-E1 cells to illustrate the exact pathogenesis mechanism.

Results: IA and SC UCMSC injections preserved cartilage, synovium, and subchondral bone parameters like trabecular bone volume fraction (BV/TV). SC injection uniquely improved Trabecular separation (Tb.Sp) and Trabecular number (Tb.N). SC and IA injections of UCMSCs demonstrated equivalent efficacy in promoting osteoblastic bone formation and attenuating aberrant angiogenesis of subchondral bone. In addition, we demonstrated that osteoblast apoptosis and Smad2-dependent TGF-beta (TGF-β) are crucial and interactive subchondral bone pathological features in OA. In vivo and vitro studies further revealed that UCMSCs inhibited excessive TGF-β/pSmad2 signaling to regulate aberrant vascularization, osteoblast apoptosis and differentiation imbalance, ultimately maintaining osteochondral homeostasis.

Conclusions: The efficacy of UCMSCs for treating OA rats via SC injection was equivalent to that of IA; and even superior to IA in terms of subchondral bone phenotype via regulating apoptosis and TGF-β/pSmad2 signaling in osteoblasts, suggesting SC injection of UCMSCs as a potential and promising cell therapy for OA treatment.

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软骨下注射人脐带间充质干细胞通过抑制成骨细胞凋亡和tgf - β活性改善膝关节骨性关节炎。

背景：骨关节炎（OA）是一种常见的退行性疾病，由多种病理机制引起，其中软骨下骨功能障碍起重要作用。尽管间充质干细胞（MSCs）的主流递送方法是通过关节内（IA）递送，但近年来，软骨下（SC）注射骨科材料引起了越来越多的关注。本研究探讨SC注射人脐带间充质干细胞（UCMSCs）对OA的影响及其可能的治疗机制，并与IA注射进行比较。方法：雄性Sprague-Dawley大鼠前交叉韧带横断（ACLT）经SC或IA注射生理盐水或UCMSC。每周连续注射1次，连续注射3周，再停药4周，随后进行x线扫描、组织病理学、免疫组织化学和末端脱氧核苷酸转移酶（TdT）介导的dUTP镍端标记（TUNEL）染色。采用细胞计数试剂盒-8 （CCK-8）、碱性磷酸酶（ALP）、茜素红染色（ARS）、TUNEL、流式细胞术、定量实时聚合酶链反应（qRT-PCR）、Western blotting等方法对tnf α诱导的MC3T3-E1细胞进行检测，探讨其确切的发病机制。结果：IA和SC UCMSC注射保存了软骨、滑膜和软骨下骨参数，如小梁骨体积分数（BV/TV）。SC注射独特地改善了小梁分离（Tb.Sp）和小梁数量（Tb.N）。SC和IA注射UCMSCs在促进成骨细胞骨形成和减弱软骨下骨异常血管生成方面具有相同的效果。此外，我们证明成骨细胞凋亡和smad2依赖性TGF-β (TGF-β)是骨性关节炎软骨下骨病理特征的关键和相互作用。体内和体外研究进一步揭示，UCMSCs通过抑制TGF-β/pSmad2过量信号通路，调节异常血管形成、成骨细胞凋亡和分化失衡，最终维持骨软骨稳态。结论：UCMSCs对SC注射治疗OA大鼠的疗效与IA相当；通过调节成骨细胞的凋亡和TGF-β/pSmad2信号传导，在软骨下骨表型方面甚至优于IA，提示SC注射UCMSCs是一种潜在且有前景的OA细胞治疗方法。

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来源期刊

Stem Cell Research & Therapy CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

13.20

自引率

8.00%

发文量

525

审稿时长

1 months

期刊介绍： Stem Cell Research & Therapy serves as a leading platform for translational research in stem cell therapies. This international, peer-reviewed journal publishes high-quality open-access research articles, with a focus on basic, translational, and clinical research in stem cell therapeutics and regenerative therapies. Coverage includes animal models and clinical trials. Additionally, the journal offers reviews, viewpoints, commentaries, and reports.