The Biomarkers Changes in Serum and the Correlation with Quantitative MRI Markers by Histopathologic Evaluation of the Cartilage in Surgically-Induced Osteoarthritis Rabbit Model

Abstract

PurposeTo investigate the biomarkers change in serum and the correlation with quantitative MRI markers by histopathologic evaluation of the cartilage in surgically-induced osteoarthritis(OA) rabbit model.Materials and MethodsThirty-six mature New Zealand rabbits were used. Eighteen rabbits were divided into six groups randomly and equally and subjected to surgery using the improved Hulth method. The other eighteen rabbits were also allocated into six groups randomly and equally which served as the control. At multiple time points after surgery, the BMP-2, CTX-II and COMP levels in the serum were analyzed by ELISA, and quantitative MRI was performed. Histopathology was examined with HE, and Mankin scores were assessed. The changes in the biochemical biomarkers and imaging markers in the OA groups were compared with those in the control groups using paired-samples T tests. The correlation of quantitative MRI markers with biomarkers and Mankin scores were analyzed. The analysis of Mankin scores was conducted with non-parametric wilcoxon signed rank tests.ResultsThe BMP-2 levels were increased at various times after surgery, and significant differences were observed between the OA and control groups(all the P values <0.001). CTX-II levels were significantly elevated at several intervals after surgery, including W2, W8, W12, W16 and W20(P=0.019, 0.004, 0.007, <0.001 and 0.016 respectively), but not at W4(P=0.764). Significant differences in the COMP levels from W2 to W20 were observed between the OA and the control groups(P<0.001, <0.001, <0.001, <0.001,=0.002 and =0.004 respectively). The T2 values increased at W8 post-surgery and were significantly different between the OA and control groups(P=0.001, <0.001, <0.001 and <0.001 respectively). T2* values increased from W2 to W20 and were significantly different between the control and OA groups(P=0.002, =0.001, <0.001, <0.001, =0.001 and <0.001 respectively). T2 values had significant correlation with BMP-2 and CTX-II(P<0.001 and =0.014), except COMP(P=0.305)., while the correlation of T2* values with BMP-2, CTX-II and COMP was significant(P=0.043, 0.005 and 0.025 respectively). In addition, a positive correlation of T2 values and Mankin scores was observed(P<0.001).ConclusionWith the relevance of the multiple time point analysis of the serum biomarkers and imaging markers compared with histological findings, BMP-2, CTX-II and COMP combined with T2 and T2* can be used to reflect and monitor OA progression potentially.

Combined detection of serum CTX-II and COMP concentrations in osteoarthritis model rabbits: an effective technique for early diagnosis and estimation of disease severity

“…We found that the serum concentration of CTX-II increased beginning as early as week 2 after surgery. The same results have been obtained in rabbits with OA induced by ACLT in a previous study [12]. These results suggest that type II collagen fibers are destroyed at a very early stage of OA development.…”

“…Cartilage oligomeric matrix protein (COMP) and crosslinked C-telopeptides of type II collagen (CTX-II) are two biochemical markers; they are degradation products of joint tissues, especially the cartilage extracellular matrix, and can potentially predict the destruction of articular cartilage in OA [12–15]. However, many studies of early OA diagnosis have only measured one of these two biomarkers at a single time point during the pathological process of OA.…”

Review of Soluble Biomarkers of Osteoarthritis: Lessons From Animal Models

“…Significant differences in the COMP levels from W2 to W20 were observed between the OA and the control groups. 16 Another research observed a significant increase of CTX-II in synovial fluid in rabbit with medial meniscectomy. 17 Moreover, highly significant correlations between synovial fluid CTX-II levels and the macroscopic and microscopic scoring results were found.…”

“…In young animals, CTX-II levels increased rapidly and reached a maximum at week 2 and then, decreased over time until the week 20. 15 In experimental OA induced by anterior and posterior cruciate ligaments transection and medial meniscus excision, Zuo et al 16 investigated the evolution of serum bone morphogenetic protein-2 (BMP-2), CTX-II, and cartilage oligomeric protein (COMP). The BMP-2 levels were increased at various times after surgery, and significant differences were observed between the OA and the control groups.…”

Investigational drugs for the treatment of osteoarthritis

“…The combination of several biochemical biomarkers, reflecting different pathways, would be more effective for predicting disease progression in knee and hip OA [116,117]. A combination of biochemical and MRI-based biomarkers may provide more effective diagnostic and prognostic tools for prediction of longitudinal OA progression [118,119]. These biomarkers may have great potential for helping DMOAD development in the future.…”