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

Abstract

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 Dark Agouti (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.

Sex-dependent variation in cartilage adaptation: from degeneration to regeneration

“…For example, BMP7 induces the production of ECM to help protect against damage from IL1, IL6, and fibronectin fragments; BMP7 is also involved in the preservation of chondrogenic potential [ 9 ]. On average, males consistently have higher BMP7 expression in cartilage, which is consistent with the lower incidence of OA in males versus females [ 137 ]. BMP2 exhibits both anabolic and catabolic effects on cartilage by inducing type II collagen and aggrecan production, promoting proteoglycan synthesis, and elevating MMP13 expression.…”

“…This growth factor was also found to upregulate several metalloproteinases, such as MMP13, ADAMTS4, and ADAMTS5, leading to the stimulation of pro-inflammatory cytokines and the inhibition of anabolic molecules, such as BMP7 [ 9 ]. Since BMP7 is typically expressed at higher concentrations in males, male cartilage may be better equipped to override the inhibitory effects of FGF2 [ 137 ]. While limited data exist regarding the relationship between sex hormones and FGFs in cartilage, a study of bovine ovarian tissue concluded that FGF18 decreased the synthesis of estrogen and progesterone production, indicating a negative correlation between female sex hormones and FGF18 in female reproductive organs [ 146 ].…”

Lead Decreases Bone Morphogenetic Protein-7 (BMP-7) Expression and Increases Renal Cell Carcinoma Growth in a Sex-Divergent Manner

“…There is evidence that BMP-7 is regulated by sex hormones. BMP-7 expression is greater in the male hippocampus than in females [ 62 ]. More directly, BMP-7 mRNA is decreased by orchidectomy and increased by testosterone and dihydrotestosterone in mouse prostate [ 63 ].…”