Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report

Wang, Guoliang; Fan, Rui; Ji, Ruirui; Zou, W.; Penny, Daniel J.; Varghese, Nidhy P.; Fan, Yuxin

doi:10.1186/s12890-016-0183-7

Cited by 75 publications

(86 citation statements)

References 12 publications

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“…However, some studies also demonstrated that BMP9 can induce MSCs to differentiate into various cell types [22,65,66]. Moreover, aberrant BMP9 expression might be involved in certain diseases [20,29,34]. These studies suggest that several signaling pathways are involved in BMP9-regulated cell fate or proliferation, but the specific pathways are unclear.…”

Section: Resultsmentioning

confidence: 99%

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Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

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30Germ cell 1 spermatogonial (GC-1spg) cells are multipotent progenitor cells. We 31 previously confirmed that bone morphogenetic protein (BMP) 9 is among the most 32 osteogenic BMPs. However, whether GC-1spg cells are driven toward osteogenic 33 differentiation under proper stimuli is uncertain. Additionally, the molecular 34 mechanism of BMP9 remains unclear. In the present study, we aimed to determine 35 whether BMP9 can induce osteogenic differentiation of GC-1spg cells. Recombinant 36 adenoviruses were generated by the AdEasy system to regulate the BMP9 expression in 37 GC-1spg cells. We identified osteogenic markers by real-time PCR and staining 38 techniques in vitro. Ectopic ossification assays and histological analysis were also 39 performed to verify the in vivo activity of BMP9. Finally, potential signaling pathways 40 of BMP9 were assessed by transcriptome sequencing and KEGG enrichment analysis. 41Using recombinant adenoviruses, we demonstrate that BMP9 upregulates osteogenic 42 markers including Runx2, osteocalcin, osteopontin, and Sox9. BMP9 also activates 43 alkaline phosphatase activity and calcium deposition in GC-1spg cells. In vivo results 44show that BMP9 overexpression in GC-1spg cells promotes ectopic bone formation and 45 chondrogenesis. In addition, RNA-sequencing and KEGG pathway analysis 3 46 demonstrate that several signaling pathways are involved in BMP9-mediated 47 osteogenesis. GC-1spg cells not only maintain spermatogenesis but also retain the 48 ability to form bone tissue. Therefore, BMP9 activity in GC-1spg cells may help 49 identify signaling pathways implicated in bone formation and could be of use in 50 regenerative medicine. 51 Keywords: Bone morphogenetic protein 9, RNA-seq, KEGG pathway analysis, 52 recombinant adenovirus, chondrogenesis 53 Introduction 54 Germ cell 1 spermatogonial (GC-1spg) cells are mouse spermatogonia that are 55 immortalized by the SV40 large T antigen [1]. These cells can differentiate into diverse cell 56 types or undergo self-renewal, depending on different factors [2,3,4]. GC-1spg cells are 57 largely involved in spermatogenesis and have mesenchymal stem cell (MSC) differentiation 58 potential [5,6,7,8]. In other words, GC-1spg cells can differentiate into different cell types, 59including those of the osteogenic, chondrogenic, or adipogenic lineages [9,10,11,12]. 60However, several molecular events [13,14] and factors are involved in osteogenic 61 differentiation of MSCs. Importantly, bone morphogenetic proteins (BMPs) are essential for 62 this process [15,16,17]. 63 BMPs, members of the TGF-β superfamily, are required for bone formation, stem cell 64 differentiation, and male reproduction [15,16,18,19,20]. Thus far, more than 15 different 65 BMPs have been identified. Our previous work showed that BMP9 is the most osteogenic 66 BMP [21,22,23,24]. BMP9, also known as growth differentiation factor 2 (GDF-2)[25], was 67 originally isolated from the fetal mouse liver [25,26]. Bone formation involves BMP9 acting 68 through the Notch signaling ...

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Section: Resultsmentioning

confidence: 99%

“…Several metabolic processes are regulated by BMP9, including glucose and lipid metabolism [28,29], iron metabolism [30], endothelial function, and angiogenesis [31,32,33]. Accordingly, abnormal BMP9 expression may be involved in various diseases [29,34,35,36].…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Loss-of-function BMPR2 mutations are the major genetic cause for PAH, and of the additional seven mutated genes identified in PAH patients to date, six are involved in the endothelial ALK1/BMPR-II pathway, of which BMP9 and BMP10 are the cognate ligands [18]. In fact, a BMP9 homozygous nonsense mutation was recently reported in a 5-year old paediatric PAH patient [19], which would be predicted to lead to absent BMP9. HHT typically presents with arteriovenous malformations (AVMs) and small vascular malformations called the telangiectases.…”

Section: The Bmp9/bmp10 Pathways In Disease and Their Therapeutic Potmentioning

confidence: 97%

Regulation of the ALK1 ligands, BMP9 and BMP10

Salmon

Jiang

et al. 2016

Biochemical Society Transactions

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Bone morphogenetic protein (BMP)9 and BMP10 are high affinity ligands for activin receptor-like kinase 1 (ALK1), a type I BMP receptor mainly expressed on vascular endothelial cells (ECs). ALK1-mediated BMP9/BMP10 signalling pathways have emerged as essential in EC biology and in angiogenesis. Several genetic mutations in the genes encoding the ligands and receptors of this pathway have been reported in two cardiovascular diseases, pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). Administration of recombinant BMP9 reverses experimental PAH in preclinical rodent models. Dalantercept, an Fc-fusion protein of the extracellular domain of ALK1 and a ligand trap for BMP9 and BMP10, is in phase II clinical trials for anti-tumour angiogenesis. Understanding the regulation of BMP9 and BMP10, at both gene and protein levels, under physiological and pathological conditions, will reveal essential information and potential novel prognostic markers for the BMP9/BMP10-targeted therapies.

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“…Pathogenesis of pulmonary hypertension often involves the abnormal vascular muscularization affecting mainly arterioles, such as the increased proliferation of vascular SMCs (Voelkel, Natarajan et al 2011, Tuder, Archer et al 2013. It has been shown that TGFβ mediated signaling is implicated in the development of pulmonary hypertension, with genetic mutations identified in several genes of this pathway including ALK1, BMPR2, endoglin, BMP9 and the downstream mediators (Goumans, Liu et al 2009, Machado, Southgate et al 2015, Wang, Fan et al 2016. BMPR2 haploinsufficiency was shown to cause pulmonary arterial hypertension (PAH) (Machado, Pauciulo et al 2001), while overexpression of BMPR2 in endothelial cells ameliorated PAH via the suppression of Smad2/3 signaling (Harper, Reynolds et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Angiocrine FSTL1 insufficiency leads to atrial and vein wall fibrosis via SMAD3 activation

Jiang

Zhang

Sun

et al. 2019

Preprint

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Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. Here we show that loss of follistatin-like protein 1 (FSTL1) in endothelial cells (Fstl1 ECKO ) led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with Fstl1 deletion in smooth muscle cells or hematopoietic cells. We further showed that there was excessive alpha-smooth muscle actin (αSMA) associated with atrial endocardia, heart valves, veins and microvessels after the endothelial FSTL1 deletion. Consistently, there was an increase of collagen deposition as demonstrated in livers of Fstl1 ECKO mutants. The SMAD3 phosphorylation was significantly enhanced and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ signaling in vascular mural cells of Fstl1 ECKO mice. The findings imply that endothelial FSTL1 is critical for the homeostasis of atria and veins and its insufficiency may favor cardiovascular fibrosis leading to heart failure.

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Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report

Cited by 75 publications

References 12 publications

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Regulation of the ALK1 ligands, BMP9 and BMP10

Angiocrine FSTL1 insufficiency leads to atrial and vein wall fibrosis via SMAD3 activation

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