Key Takeaways & Executive Findings
- •• A novel combined D-galactose injection and anterior cruciate ligament transection (ACLT) method successfully establishes a stable aging-related knee osteoarthritis model in SD rats. • The combined model exhibits more severe cartilage degeneration, synovial inflammation, and chondrocyte senescence compared to either D-galactose or ACLT alone. • The model shows increased chondrocyte cell cycle arrest at G0/G1 phase, elevated senescence-associated β-galactosidase activity, and DNA damage response (γ-H2AX), indicating cellular senescence. • This model better mimics the pathological features of aging-related knee osteoarthritis and provides a valuable tool for studying the mechanisms and therapeutic interventions of the disease.
Abstract
BACKGROUND: Knee osteoarthritis is an age-related disease, and aging is closely related to its occurrence and development. Chondrocyte senescence plays a crucial role in the pathological progression of knee osteoarthritis. OBJECTIVE: To establish a stable induced knee osteoarthritis model in SD rats. METHODS: (1) Animal experiment: Forty Sprague-Dawley rats were randomly divided into four groups: blank control group (no modeling), D-galactose group (intra-articular injection of D-galactose solution once a week for 2 months), anterior cruciate ligament transection (ACLT) group (ACLT to establish knee osteoarthritis model), and D-galactose+ACLT group (ACLT followed by intra-articular injection of D-galactose solution once a week for 2 months). One week after modeling, all rats underwent running exercise for 30 min every other day. At 4 and 8 weeks after modeling, behavioral tests (Lequesne MG score) were performed, and then samples were collected for detection of inflammatory factors in synovial fluid, histopathological morphology of knee cartilage, transmission electron microscopy observation, and immunohistochemical staining of type II collagen and aggrecan. (2) Cell experiment: At 4 and 8 weeks after modeling, knee chondrocytes were isolated from each group for flow cytometry cell cycle analysis, β-galactosidase staining, and γ-H2AX immunofluorescence staining. RESULTS AND CONCLUSION: (1) Animal experiment: At 8 weeks after modeling, Lequesne MG scores in the three model groups were higher than those in the blank control group (P < 0.05), and the score in the D-galactose+ACLT group was higher than that in the D-galactose and ACLT groups (P < 0.05). At 4 and 8 weeks, levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in synovial fluid were higher in the three model groups than in the blank control group (P < 0.05), and these levels were higher in the D-galactose+ACLT group than in the D-galactose and ACLT groups (P < 0.05). Hematoxylin-eosin and safranin O/fast green staining and transmission electron microscopy at 4 and 8 weeks showed that cartilage damage and chondrocyte mitochondrial damage were more severe in the D-galactose+ACLT group than in the D-galactose and ACLT groups. Immunohistochemical staining showed that the expression of type II collagen and aggrecan was highest in the blank control group, and lowest in the D-galactose+ACLT group among the model groups. (2) Cell experiment: At 4 and 8 weeks, the proportion of chondrocytes in G0/G1 phase was higher, and the proportions in S and G2/M phases were lower in the D-galactose+ACLT group than in the other three groups (P < 0.05). The positive rate of β-galactosidase staining and γ-H2AX immunofluorescence intensity were higher in the D-galactose+ACLT group than in the other three groups (P < 0.05). (3) These results indicate that the D-galactose+ACLT method can establish an SD rat model of aging-related knee osteoarthritis, which can better simulate the pathological state of aging and degeneration in knee osteoarthritis.
1. Introduction
Knee osteoarthritis is a chronic degenerative joint disease that predominantly affects middle-aged and elderly populations, manifesting as pain, swelling, joint deformity, and functional impairment, which severely impacts patients' quality of life [1-2]. The pathogenesis of knee osteoarthritis remains unclear, and exploring its mechanisms is a key focus for prevention and treatment. Studies have shown that knee osteoarthritis is an age-related disease, and aging is closely associated with its occurrence and development, with chondrocyte senescence playing a critical role in the pathological progression of knee osteoarthritis [3-4].
Animal models of diseases are essential for studying pathological mechanisms and are a crucial prerequisite for biomedical research [5-6]. An ideal animal model should closely mimic the pathogenesis and clinical manifestations of human diseases, while also considering simplicity, reproducibility, mortality, and cost-effectiveness [7]. Currently, various methods exist for establishing knee osteoarthritis models, including Hulth's method, anterior cruciate ligament transection (ACLT), intra-articular injection of monosodium iodoacetate or papain, and others. However, these models often fail to fully replicate the aging-related aspects of the disease. Therefore, this study aimed to establish a stable induced aging-related knee osteoarthritis model in SD rats by combining D-galactose injection (to induce systemic aging) with ACLT (to induce mechanical instability), and to validate the model through comprehensive assessments.
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WU Zugui, ZHU Yue, LI Jiao, YUAN Rong, WU Zhiwei, LI Junyi, LI Congcong, SHEN Zhen, GUO Ying (2026). Establishment and validation of a Sprague-Dawley rat model of aging-related knee osteoarthritis. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21529
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Frequently Asked Questions
What is the purpose of this study?
The purpose of this study was to establish a stable induced aging-related knee osteoarthritis model in SD rats by combining D-galactose injection and anterior cruciate ligament transection (ACLT), and to validate the model through comprehensive assessments.
How was the aging-related knee osteoarthritis model established?
The model was established by combining anterior cruciate ligament transection (ACLT) with intra-articular injection of D-galactose solution (once a week for 2 months) in SD rats. This combined approach was compared with D-galactose alone, ACLT alone, and blank control groups.
What were the key findings of the study?
The combined D-galactose+ACLT model exhibited more severe cartilage degeneration, higher synovial inflammation, increased chondrocyte senescence (higher G0/G1 arrest, β-galactosidase activity, and γ-H2AX expression) compared to single-method models, better mimicking the aging-related pathological state of knee osteoarthritis.
Why is this model important for knee osteoarthritis research?
This model better simulates the aging-related degenerative pathology of knee osteoarthritis, providing a valuable tool for studying the mechanisms of the disease and for evaluating potential therapeutic interventions targeting aging and senescence.
What methods were used to validate the model?
The model was validated through behavioral tests (Lequesne MG score), synovial fluid inflammatory cytokine levels (IL-1β, IL-6, TNF-α), histopathological staining (H&E, safranin O/fast green), transmission electron microscopy, immunohistochemistry for type II collagen and aggrecan, and cellular assays including flow cytometry, β-galactosidase staining, and γ-H2AX immunofluorescence.
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