Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis

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) media...

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Autores principales:	Hrvoje Omrčen, Sanja Zoričić Cvek, Lara Batičić, Sandra Šućurović, Tanja Grubić Kezele
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	bone morphogenetic proteins rheumatoid arthritis interleukin-17 tumor necrosis factor-alpha hippocampus adult neurogenesis Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/2a9f42f7407f4ee49a076b760c8d6f8f
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spelling	oai:doaj.org-article:2a9f42f7407f4ee49a076b760c8d6f8f2021-11-25T17:53:55ZGender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis10.3390/ijms2222121631422-00671661-6596https://doaj.org/article/2a9f42f7407f4ee49a076b760c8d6f8f2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12163https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067BMPs 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 <i>Dark Agouti</i> (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<sup>+</sup> and SOX-2<sup>+</sup> and DCX<sup>+</sup> cells and in the ratio of DCX<sup>+</sup> to Ki67<sup>+</sup> cells in the dentate gyrus during PIA. However, in PIA remission, females showed a faster increase in the number of Ki67<sup>+</sup>, SOX-2<sup>+</sup>, and DCX<sup>+</sup> 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.Hrvoje OmrčenSanja Zoričić CvekLara BatičićSandra ŠućurovićTanja Grubić KezeleMDPI AGarticlebone morphogenetic proteinsrheumatoid arthritisinterleukin-17tumor necrosis factor-alphahippocampusadult neurogenesisBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12163, p 12163 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	bone morphogenetic proteins rheumatoid arthritis interleukin-17 tumor necrosis factor-alpha hippocampus adult neurogenesis Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	bone morphogenetic proteins rheumatoid arthritis interleukin-17 tumor necrosis factor-alpha hippocampus adult neurogenesis Biology (General) QH301-705.5 Chemistry QD1-999 Hrvoje Omrčen Sanja Zoričić Cvek Lara Batičić Sandra Šućurović Tanja Grubić Kezele Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis
description	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 <i>Dark Agouti</i> (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<sup>+</sup> and SOX-2<sup>+</sup> and DCX<sup>+</sup> cells and in the ratio of DCX<sup>+</sup> to Ki67<sup>+</sup> cells in the dentate gyrus during PIA. However, in PIA remission, females showed a faster increase in the number of Ki67<sup>+</sup>, SOX-2<sup>+</sup>, and DCX<sup>+</sup> 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.
format	article
author	Hrvoje Omrčen Sanja Zoričić Cvek Lara Batičić Sandra Šućurović Tanja Grubić Kezele
author_facet	Hrvoje Omrčen Sanja Zoričić Cvek Lara Batičić Sandra Šućurović Tanja Grubić Kezele
author_sort	Hrvoje Omrčen
title	Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis
title_short	Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis
title_full	Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis
title_fullStr	Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis
title_full_unstemmed	Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis
title_sort	gender-related differences in bmp expression and adult hippocampal neurogenesis within joint-hippocampal axis in a rat model of rheumatoid arthritis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2a9f42f7407f4ee49a076b760c8d6f8f
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Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis

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