The present study aimed to detect early changes in the concentration of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a rat model of brain injury combined with traumatic heterotopic ossification (HO). A total of 132 male Sprague-Dawley rats were used to establish the experimental and control groups. Anatomy and sample collection were conducted on postoperative days 1, 2, 3, 4, 5, 6 and 7. Hematoxylin and eosin and immunohistochemical staining were performed for local tissues. MMP-9, MMP-2 and TIMP-1 levels and gene expression level were measured by ELISA and reverse transcription-quantitative polymerase chain reaction. Radiological investigation of the rat lower limbs was conducted at weeks 5 and 10 following modeling to observe the occurrence of HO. The incidence of HO for rats in the experimental group was higher compared with the control group. The serum MMP-9 levels of the experimental group were notably higher on postoperative days 5–7 compared with the control group. The MMP-9 gene expression of the experimental group was higher on postoperative days 3–7 compared with the control group. The TIMP-1 gene expression levels were markedly higher compared with the control group at each time point. Thus, an increase in inflammatory response is closely associated with brain injury, in addition to an increase in the number of inflammatory cells with the incidence of HO. The pathological elevation of MMP-9 and the altered dynamic equilibrium between MMP-9 and TIMP-1 contributed to the degradation, remodeling and calcification of the extracellular matrix, resulting in the induction of osteoblast precursor cells in HO. MMP-9 is a predictive marker of HO.
Objective This study aims to determine expression profiles of relevant genes in the early stages of post-traumatic heterotopic ossification (HO) in a rat model of Achilles tenotomy. Methods A total of 80 male Sprague-Dawley rats were randomly assigned to two groups: the HO group and the control group. Tenotomy was performed in the Achilles tendon of the rats in the HO group, and no intervention was conducted in the control group. On the 3 rd , 5 th , 8 th , and 14 th days after the operation, 8 rats were taken from each group at each time point, and the Achilles tendon and surrounding tissue specimens were collected. Gene expressions of TGF-β, BMP, GDF, IL, and MMP families as well as TNF-α, HIF-1α chordin, gremlin, noggin, and NODAL were analyzed by qRT-PCR. The relevant genes that were highly expressed at different time points were screened, and immunohistochemical staining was then used to verify their expression. At the 10th week, HO formation was explored by radiographic and histological examination in the remaining 8 rats of each group. Results Both the radiographic and histological analyses indicated that all the rats developed HO in the HO group (100%), whereas no HO occurred in the control group. Surrounding tissues obtained from the HO group showed significantly higher gene expressions of TGF-β1, BMP-1, IL1β, HIF-1α, and MMP-2 but lower expressions of BMP-4, GDF-8, and TNF-α compared with the control group. In addition, immunohistochemical staining confirmed the higher protein expression levels of relevant genes in the HO group. Conclusion TGF-β1, BMP-1, IL-1β, HIF-1α, MMP-2, BMP4, GDF-8, and TNF-α may be associated with the formation of traumatic HO; and BMP4, GDF-8, and TNF-α may play a protective role in the early stage of HO. In this study, we investigated the expression levels of the related cytokines in the early stages of traumatic HO in the Achilles tendon tenotomy rat model to better understand the pathogenesis of HO.
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