Department of Anatomy, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
Int J Mol Sci. 2021 Nov 10;22(22):12163. doi: 10.3390/ijms222212163.
BMPs regulate synovial quiescence and adult neurogenesis in the hippocampus in non-stress conditions. However, changes in BMP expression that are induced by inflammation during rheumatoid arthritis (RA) have not yet been reported. Here, we show that signalling with synovial BMPs (BMP-4 and -7) mediates the effect of systemic inflammation on adult neurogenesis in the hippocampus during pristane-induced arthritis (PIA) in (DA) rats, an animal model of RA. Moreover, we show gender differences in BMP expressions and their antagonists (Noggin and Gremlin) during PIA and their correlations with the clinical course and IL-17A and TNF-α levels in serum. Our results indicate gender differences in the clinical course, where male rats showed earlier onset and earlier recovery but a worse clinical course in the first two phases of the disease (onset and peak), which correlates with the initial increase of serum IL-17A level. The clinical course of the female rats worsened in remission. Their prolonged symptoms could be a reflection of an increased TNF-α level in serum during remission. Synovial inflammation was greater in females in PIA-remission with greater synovial BMP and antagonist expressions. More significant correlations between serum cytokines (IL-17A and TNF-α), and synovial BMPs and their antagonists were found in females than in males. On the other hand, males showed an increase in hippocampal BMP-4 expression during the acute phase, but both genders showed a decrease in antagonist expressions during PIA in general. Both genders showed a decrease in the number of Ki-67 and SOX-2 and DCX cells and in the ratio of DCX to Ki67 cells in the dentate gyrus during PIA. However, in PIA remission, females showed a faster increase in the number of Ki67, SOX-2, and DCX cells and a faster increase in the DCX/Ki67 ratio than males. Both genders showed an increase of hippocampal BMP-7 expression during remission, although males constantly showed greater BMP-7 expression at all time points. Our data show that gender differences exist in the BMP expressions in the periphery-hippocampus axis and in the IL-17A and TNF-α levels in serum, which could imply differences in the mechanisms for the onset and progression of the disease, the clinical course severity, and adult neurogenesis with subsequent neurological complications between genders.
BMPs 调节滑膜静止和海马体中的成年神经发生，在非应激条件下。然而，类风湿关节炎 (RA) 炎症诱导的 BMP 表达变化尚未报道。在这里，我们表明滑膜 BMPs（BMP-4 和 -7）信号转导介导了全身性炎症对 pristane 诱导的关节炎 (PIA) 期间成年神经发生的影响。在动物模型中。此外，我们还展示了在 PIA 期间，BMP 及其拮抗剂（ Noggin 和 Gremlin）在性别之间的表达差异及其与临床病程以及血清中 IL-17A 和 TNF-α 水平的相关性。我们的结果表明，在临床病程中存在性别差异，其中雄性大鼠表现出更早的发病和更早的恢复，但在疾病的前两个阶段（发病和峰值）的临床病程更差，这与血清 IL-17A 水平的初始增加有关。雌性大鼠的临床病程在缓解期恶化。她们的长期症状可能反映了缓解期血清 TNF-α 水平的增加。在 PIA-缓解期，女性滑膜炎症更严重，滑膜 BMP 和拮抗剂表达更高。与男性相比，女性血清细胞因子（IL-17A 和 TNF-α）与滑膜 BMP 和拮抗剂之间的相关性更为显著。另一方面，男性在急性期表现出海马 BMP-4 表达增加，但两性在 PIA 期间一般表现出拮抗剂表达减少。在 PIA 期间，两性在齿状回中均表现出 Ki-67 和 SOX-2 以及 DCX 细胞数量减少，以及 DCX 与 Ki67 细胞的比值减少。然而，在 PIA 缓解期，女性的 Ki67、SOX-2 和 DCX 细胞数量增加更快，DCX/Ki67 比值增加更快。两性在缓解期均表现出海马 BMP-7 表达增加，尽管男性在所有时间点始终表现出更高的 BMP-7 表达。我们的数据表明，外周-海马轴的 BMP 表达以及血清中的 IL-17A 和 TNF-α 水平存在性别差异，这可能意味着疾病发作和进展、临床病程严重程度以及成年神经发生的机制存在差异。性别之间的神经并发症。
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