Suppression of TGFβR-Smad3 pathway alleviates the syrinx induced by syringomyelia

Abstract

Background Syringomyelia is a cerebrospinal fluid (CSF) disorder resulted in separation of pain and temperature, dilation of central canal and formation of syrinx in central canal. It is unclear about mechanisms of the dilation and syrinx formation. We aimed to investigate roles of ependymal cells lining central canal on the dilation, trying to reduce syrinx formation in central canal. Methods We employed 78 Sprague–Dawley (SD) rats totally with syringomyelia to detect the contribution of ependymal cells to the dilation of central canal. Immunofluorescence was used to examine the activation of ependymal cells in 54 syringomyelia rat models. BrdU was used to indicate the proliferation of ependymal cells through intraperitoneal administration in 6 syringomyelia rat models. 18 rats with syringomyelia were injected with SIS3, an inhibitor of TGFβR-Smad3, and rats injected with DMSO were used as control. Among the 18 rats, 12 rats were used for observation of syrinx following SIS3 or DMSO administration by using magnetic resonance imaging (MRI) on day 14 and day 30 under syringomyelia without decompression. All the data were expressed as mean ± standard deviation (mean ± SD). Differences between groups were compared using the two-tailed Student’s t-test or ANOVA. Differences were considered significant when *p < 0.05. Results Our study showed the dilation and protrusions of central canal on day 5 and enlargement from day 14 after syringomyelia induction in rats with activation of ependymal cells lining central canal. Moreover, the ependymal cells contributed to protrusion formation possibly through migration along with central canal. Furthermore, suppression of TGFβR-Smad3 which was crucial for migration reversed the size of syrnix in central canal without treatment of decompression, suggesting TGFβR-Smad3 signal might be key for dilation of central canal and formation of syrinx. Conclusions The size of syrinx was decreased after SIS3 administration without decompression. Our study depicted the mechanisms of syrinx formation and suggested TGFβR-Smad3 signal might be key for dilation of central canal and formation of syrinx.

TGF-β signaling in health, disease and therapeutics

“…[1046][1047][1048] Meanwhile, SMAD3 antisense oligonucleotide treatment was found to improve flexor tendon repair in mice and might have possible therapeutic applications in clinical practice. 877 Moreover, a small-molecule SMAD3 inhibitor known as specific inhibitor of SMAD3 (SIS3) has shown pre-clinical therapeutic efficacy in wound healing, 1049 cardiovascular diseases, 569,1050,1051 nervous diseases, 1052 renal diseases, 1053,1054 skeletal diseases, 1055 fibrotic diseases, 1056,1057 inflammatory diseases, 1039,1058 type 2 diabetes, 1059,1060 and tumors, 1061,1062 suggesting a novel approach that could be further tested to treat clinical patients.…”