β-Sitosterol preconditioning enhances the resistance of BMSCs and chondrocyte to oxidative stress and promotes cartilage repair in osteoarthritis

Abstract

Background Osteoarthritis (OA) is a joint disorder that severely affects patients’ mobility, overall health, and ability to perform daily activities. Despite advancements in therapeutic strategies, stem cell-based therapies for OA still face challenges, particularly in enhancing the antioxidative capacity of stem cells to improve therapeutic outcomes. Therefore, this study aimed to explore the potential of β-sitosterol in this context. Methods This study evaluated the protective effects of β-sitosterol on bone marrow-derived mesenchymal stem cells (BMSCs) and chondrocytes under oxidative stress conditions and assessed its potential in promoting cartilage repair in a rabbit OA model. Cell viability, gene expression, oxidative stress markers, and mitochondrial function were examined. In vivo therapeutic effects were evaluated through histological and immunohistochemical analyses. Results The results revealed that β-sitosterol significantly enhanced BMSC viability, upregulated the expression of Col2a1 and aggrecan, while inhibiting MMP13 expression. Furthermore, β-sitosterol effectively alleviated oxidative stress and preserved mitochondrial function in BMSCs. Notably, BMSCs pretreated with β-Sitosterol exhibited a higher potential for facilitating cartilage regeneration in the OA model, as evidence by histopathological analysis. Conclusions These findings suggest that β-sitosterol possesses significant antioxidative and chondroprotective properties, which enhance the therapeutic efficacy of BMSCs in addressing OA-related cartilage damage.

1. Introduction

Osteoarthritis (OA) is one of the most prevalent skeletal disorders and a leading cause of mobility impairment among the aging population. Despite extensive studies, with no effective cure for OA is currently available [1–3]. OA is characterized primarily by the progressive degradation of articular cartilage. Conventional therapeutic approaches, including hyaluronic acid injections, joint replacement, and non-steroidal anti-inflammatory drugs, are primarily palliative, offering symptomatic relief but failing to promote cartilage regeneration or halt disease progression. Moreover, these treatments are often associated with notable adverse effects, particularly with long-term use [2, 4, 5]. Thus, there is an urgent need to develop new regenerative strategies capable of addressing the underlying pathology of OA and facilitating cartilage repair, which holds considerable promise for improving clinical outcomes.

Recently, BMSCs have emerged as a promising therapeutic approach for cartilage repair in OA, attributed to their pluripotent differentiation potential and immunoregulatory properties [6, 7]. Significant progress has been achieved in preclinical studies using animal models, with some BMSC-based therapies already demonstrating promising results [8, 9]. For instance, intra-articular injection of BMSCs has demonstrated efficacy in mitigating pathological symptoms of mild to moderate OA by alleviating cartilage degradation and subchondral bone damage [10, 11]. Nonetheless, the oxidative stress microenvironment in OA lesions posed a major challenge, significantly impairing the survival, engraftment, and treatment efficacy of transplanted BMSCs.

β-Sitosterol, a natural bioactive ingredient, has been broadly utilized in the medical and health food industries [12, 13]. Previous studies have demonstrated that β-sitosterol significantly ameliorates tissue damage in cardiovascular and neurodegenerative diseases by inhibiting reactive oxygen species (ROS) production [14, 15]. Furthermore, network pharmacology analysis has identified 13 shared targets between β-sitosterol and OA, including key proteins like Bcl2, CASP3, and CASP8, suggesting its potential value in OA management [16]. To date, the effects of β-sitosterol on OA treatment, particularly its role in modulating antioxidative stress in BMSCs and chondrocytes, remain largely unexplored.