Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis

Shijo, Tomomi; Warita, Hitoshi; Suzuki, Naoki; Ikeda, Kensuke S.; Mitsuzawa, Shio; Akiyama, Tetsuya; Ono, Hiroya; Nishiyama, Ayumi; Izumi, Rumiko; Kitajima, Yasuo; Akiyama, Masashi

doi:10.1016/j.expneurol.2018.06.009

Cited by 12 publications

(20 citation statements)

References 46 publications

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“…Considering that only 12 TFs (out of 1211 human TFs) belong to the gliosis-associated gene module identified in MS SCs, the presence of SMAD1 and SOX2 in the short list of currently known HOXA5 TF partners corresponds to an enrichment factor of 31.74 with an associated p-value of 0.002 (Fisher’s exact test). Of note, several works demonstrated the progliotic effects of SOX2 and SMAD1 [39,40,41]. Furthermore, SMAD1 belongs to the BMP (bone morphogenetic protein) and to the TGFB1 signaling pathways [42,43,44,45], both of which have been involved in astrocytosis [46,47].…”

Section: Resultsmentioning

confidence: 99%

TGFB1-Mediated Gliosis in Multiple Sclerosis Spinal Cords Is Favored by the Regionalized Expression of HOXA5 and the Age-Dependent Decline in Androgen Receptor Ligands

Nataf

Guillen

Pays

2019

IJMS

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In multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord (SC) functions slowly deteriorate beyond age 40. We previously showed that in the SC of these patients, large areas of incomplete demyelination extend distance away from plaque borders and are characterized by a unique progliotic TGFB1 (Transforming Growth Factor Beta 1) genomic signature. Here, we attempted to determine whether region- and age-specific physiological parameters could promote the progression of SC periplaques in MS patients beyond age 40. An analysis of transcriptomics databases showed that, under physiological conditions, a set of 10 homeobox (HOX) genes are highly significantly overexpressed in the human SC as compared to distinct brain regions. Among these HOX genes, a survey of the human proteome showed that only HOXA5 encodes a protein which interacts with a member of the TGF-beta signaling pathway, namely SMAD1 (SMAD family member 1). Moreover, HOXA5 was previously found to promote the TGF-beta pathway. Interestingly, SMAD1 is also a protein partner of the androgen receptor (AR) and an unsupervised analysis of gene ontology terms indicates that the AR pathway antagonizes the TGF-beta/SMAD pathway. Retrieval of promoter analysis data further confirmed that AR negatively regulates the transcription of several members of the TGF-beta/SMAD pathway. On this basis, we propose that in progressive MS patients, the physiological SC overexpression of HOXA5 combined with the age-dependent decline in AR ligands may favor the slow progression of TGFB1-mediated gliosis. Potential therapeutic implications are discussed.

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Section: Resultsmentioning

confidence: 99%

TGFB1-Mediated Gliosis in Multiple Sclerosis Spinal Cords Is Favored by the Regionalized Expression of HOXA5 and the Age-Dependent Decline in Androgen Receptor Ligands

Nataf

Guillen

Pays

2019

IJMS

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“…In humans, elevated BMP signals disrupted the normal development of the palate and teeth [31,32]. Other studies demonstrated that BMP4 is related to the malformation of tissues and organs, such as dysplasia of the lumbosacral spinal cord in rats [33], in multiplex nonsyndromic cleft lip with or without cleft palate in humans [34,35], and in enhancing astrocytosis, microgliosis, and amyotrophic lateral sclerosis [36]. Furthermore, the ectopic osteogenesis of fibrodysplasia ossificans progressiva is associated with overexpression of BMP4 in lymphocytes, which suggests that an inappropriate enhancement of BMP4 expression may play an essential role in the molecular pathophysiology of fibrodysplasia ossificans progressiva [37,38].…”

Section: Discussionmentioning

confidence: 99%

The Morphology of Cross-Beaks and BMP4 Gene Expression in Huiyang Bearded Chickens

Hong

Pang

Zhao

et al. 2019

Animals

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Bird beaks are important for biological purposes such as food intake, removing parasites, and defining phenotypic attributes. Cross-beaks are a threat to poultry health and are harmful to productivity, wasting some units in the poultry industry. However, there is still limited research on subtypes of cross-beaks and the genetic basis of cross-beaks as well. Here, we described the subtypes of cross-beaks in terms of left or right and upper or lower jaw bones. We evaluated the impact of cross-beaks on craniofacial bones and figured out the relationship between bone morphogenetic protein 4 (BMP4) and the development of craniofacial bones in Huiyang bearded chickens. We identified five typical subtypes of cross-beaks by morphological assessment and X-ray scanning. We found that cross-beaks caused certain changes in the facial bone morphology, including changes to the length and width of the bone around the ocular area (p < 0.05). The relative expressions of BMP4 in lacrimal, mandible, premaxilla, frontal, and parietal bones were significantly higher in the severe cross-beak group, followed by that of the medium cross-beak group, weak cross-beak group, and control group (p < 0.05). Overall, we constructed a generally applicable method to classify cross-beaks in term of the angle. The skeleton around the ocular area was affected by the cross-beak. The expression levels of BMP4 in craniofacial bones may provide insight to potential role of BMP4 in the development of cross-beaks.

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“…Indomethacin, a non-steroidal anti-inflammatory drug, significantly reduced microglial activation in a rat model of focal ischemia model (Lopes et al, 2016 ). Noggin is an endogenous antagonist of bone morphogenetic proteins (BMPs) such as BMP 2 and BMP 4 (Shijo et al, 2018 ; Chien et al, 2020 ). In a rat model of amyotrophic lateral sclerosis, antagonizing BMP4 attenuated disease progression through suppressing microglia and astrocyte activation, and noggin supplementation significantly ameliorated the progression of the disease, suggesting that noggin might modulate glia function through regulating BMPs (Shijo et al, 2018 ).…”

Section: Microglia As Therapeutic Targets For Ischemic Brain Injuriesmentioning

confidence: 99%

“…Noggin is an endogenous antagonist of bone morphogenetic proteins (BMPs) such as BMP 2 and BMP 4 (Shijo et al, 2018 ; Chien et al, 2020 ). In a rat model of amyotrophic lateral sclerosis, antagonizing BMP4 attenuated disease progression through suppressing microglia and astrocyte activation, and noggin supplementation significantly ameliorated the progression of the disease, suggesting that noggin might modulate glia function through regulating BMPs (Shijo et al, 2018 ). In the MCAO mice model, noggin was found to be involved in the regulation of microglia polarization.…”

Section: Microglia As Therapeutic Targets For Ischemic Brain Injuriesmentioning

confidence: 99%

Microglia and Their Promising Role in Ischemic Brain Injuries: An Update

et al. 2020

Front. Cell. Neurosci.

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Ischemic brain injuries are common diseases with high morbidity, disability, and mortality rates, which have significant impacts on human health and life. Microglia are resident cells of the central nervous system (CNS). The inflammatory responses mediated by microglia play an important role in the occurrence and development of ischemic brain injuries. This article summarizes the activation, polarization, depletion, and repopulation of microglia after ischemic brain injuries, proposing new treatment strategies for such injuries through the modulation of microglial function.

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Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis

Cited by 12 publications

References 46 publications

TGFB1-Mediated Gliosis in Multiple Sclerosis Spinal Cords Is Favored by the Regionalized Expression of HOXA5 and the Age-Dependent Decline in Androgen Receptor Ligands

TGFB1-Mediated Gliosis in Multiple Sclerosis Spinal Cords Is Favored by the Regionalized Expression of HOXA5 and the Age-Dependent Decline in Androgen Receptor Ligands

The Morphology of Cross-Beaks and BMP4 Gene Expression in Huiyang Bearded Chickens

Microglia and Their Promising Role in Ischemic Brain Injuries: An Update

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