Key Takeaways & Executive Findings
- •• Subchondral injection of UCMSCs significantly improves trabecular microarchitecture (Tb.Sp, Tb.N) in OA rats, outperforming intra-articular injection in these specific parameters. • Both subchondral and intra-articular UCMSC injections effectively preserve cartilage, synovium, and subchondral bone, and promote osteoblastic bone formation while reducing aberrant angiogenesis. • The therapeutic mechanism involves inhibition of excessive TGF-β/pSmad2 signaling, which in turn reduces osteoblast apoptosis and restores bone remodeling balance. • Subchondral delivery of MSCs represents a promising, potentially superior route for treating OA by directly targeting subchondral bone pathology.
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 osteoblast apoptosis and bone remodeling, thereby ameliorating OA progression. These findings suggest that SC injection of UCMSCs is a promising therapeutic strategy for OA, potentially offering advantages over IA injection in improving subchondral bone microarchitecture.
1. Introduction
Osteoarthritis (OA) is a common disorder characterized by articular cartilage degeneration, subchondral bone remodeling, meniscal deterioration, synovial inflammation and aberrant vascularization [1, 2]. Although established risk factors including genetic predisposition, mechanical overload, aging, and obesity are well-documented, the precise pathogenic mechanisms driving OA remain unresolved [3]. The last three decades have seen a growing incidence rate of OA as societies age, with estimated annual percentage change of 0.32% [4, 5]. Currently, over 595 million individuals worldwide lived with OA and numbers are predicted to increase up until 2050, placing a larger strain on the health-system burden globally [6]. Unfortunately, the treatments up to now are mostly symptom-relieving, and disease-modified treatment is still lacking because the exact pathogenesis of OA remains unclear [7].
Although commonly described as a wear-and-tear disease, OA is now recognized as a whole-joint pathology involving multiple tissue components [8]. Emerging evidence highlights the pathological significance of meniscal degeneration and infrapatellar fat pad remodeling in OA progression [9, 10]. Notably, subchondral bone microarchitectural alterations and associated histopathological changes have been identified as equally crucial to articular cartilage degeneration in OA pathogenesis, demonstrating comparable etiological importance [11, 12]. The homeostasis of the subchondral bone relies on coupled bone remodeling, namely osteoblast-mediated bone formation and osteoclast-mediated resorption. Accelerated subchondral bone turnover is seen in the early stages, whereas the subchondral bone sclerosis is observed during the advanced and late stages [13]. However, the high bone turnover leads to insufficient bone mineralization, thus compromising mechanical property of the newly formed bone [14]. Additionally, evidence also shown that H-type vessels with high CD31 expression aggravate subchondral angiogenesis and aberrant osteogenesis [15]. Osteoblast plays a critical role in the maintenance of normal bone remodeling. Although apoptosis is essential to physiological bone turn over, overactivated apoptosis will result in osteoblast dysfunctions, reducing osteoblast num
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Congzi Wu, HuiHui Xu, Zhen Wu, Haipeng Huang, Qinwen Ge, Jianbo Xu, Jiali Chen, Pinger Wang, Wenhua Yuan, Hongting Jin, Peijian Tong (2026). Subchondral injection of human umbilical cord mesenchymal stem cells ameliorates knee osteoarthritis by inhibiting osteoblast apoptosis and TGF-beta activity. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04366-7
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that subchondral injection of human umbilical cord mesenchymal stem cells (UCMSCs) ameliorates knee osteoarthritis by inhibiting osteoblast apoptosis and TGF-beta activity, with unique improvements in trabecular microarchitecture compared to intra-articular injection.
How does subchondral injection compare to intra-articular injection?
Both routes effectively preserve cartilage and subchondral bone, but subchondral injection uniquely improves trabecular separation and number, suggesting a potential advantage in targeting subchondral bone pathology.
What is the proposed mechanism of UCMSCs in treating OA?
UCMSCs inhibit excessive TGF-β/pSmad2 signaling, which reduces osteoblast apoptosis and restores bone remodeling balance, thereby ameliorating OA progression.
What animal model was used in this study?
The study used male Sprague-Dawley rats with anterior cruciate ligament transection (ACLT) to induce osteoarthritis.
What are the clinical implications of this research?
Subchondral injection of UCMSCs could be a promising therapeutic strategy for OA, potentially offering a more targeted approach to subchondral bone abnormalities compared to conventional intra-articular injections.
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