BMP-9 interferes with liver regeneration and promotes liver fibrosis

Breitkopf‐Heinlein, Katja; Meyer, Christoph; König, Courtney; Gaitantzi, H; Addante, Annalisa; Thomas, Maria; Wiercinska, Eliza; Cai, Chen; Li, Qi; Wan, Fengqi; Hellerbrand, Claus; Valous, Nektarios A.; Hahnel, Maximilian J.; Ehlting, Christian; Bode, Johannes G.; Müller-Bohl, Stephanie; Klingmüller, Ursula; Altenöder, Jutta; Ilkavets, Iryna; Goumans, Marie–José; Hawinkels, Lukas J.A.C.; Lee, Se-Jin; Wieland, Matthias; Mogler, Carolin; Ebert, Matthias P.; Herrera, Blanca; Augustin, Hellmut G.; Sánchez, Aránzazu; Dooley, Steven; Dijke, Peter ten

doi:10.1136/gutjnl-2016-313314

Cited by 116 publications

(151 citation statements)

References 57 publications

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“…Both BMP-2 and BMP-6 can similarly attenuate kidney fibrosis in rodent models of kidney disease (Yang et al, 2009; Dendooven et al, 2011), and BMP-6 expression is increased in humans and mice suffering non-alcoholic fatty liver disease (NAFLD) and is protective for hepatic fibrosis (Arndt et al, 2015). Interestingly, loss of BMP-4 is speculated to drive opposing pro-fibrotic response in cardiac tissue (Sun et al, 2013), and increased BMP-9 in the liver induces a fibrotic-like response (Breitkopf-Heinlein et al, 2017). …”

Section: Activators Of the Smad-1/5 Axis And Fibrosismentioning

confidence: 99%

Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis

2017

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Fibrosis occurs when there is an imbalance in extracellular matrix (ECM) deposition and degradation. Excessive ECM deposition results in scarring and thickening of the affected tissue, and interferes with tissue and organ homeostasis – mimicking an exaggerated “wound healing” response. Many transforming growth factor-β (TGF-β) ligands are potent drivers of ECM deposition, and additionally, have a natural affinity for the ECM, creating a concentrated pool of pro-fibrotic factors at the site of injury. Consequently, TGF-β ligands are upregulated in many human fibrotic conditions and, as such, are attractive targets for fibrosis therapy. Here, we will discuss the contribution of TGF-β proteins in the pathogenesis of fibrosis, and promising anti-fibrotic approaches that target TGF-β ligands.

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Section: Activators Of the Smad-1/5 Axis And Fibrosismentioning

confidence: 99%

Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis

2017

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“…Bone morphogenetic protein 9 (BMP9) (also known as growth differentiation factor 2, or GDF‐2), a member of the transforming growth factor‐β (TGF‐β)/BMP superfamily, is principally produced by the liver and circulates in the bloodstream; its receptors are ALK1 and ALK2 . Recent research has found that BMP9 plays an important role in preventing liver fibrosis, improving heart failure, suppressing tumors, regulating glucose and lipid metabolism, and regenerating joints .…”

Section: Introductionmentioning

confidence: 99%

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Zhou

Yang

Jing

et al. 2020

Journal of Bone and Mineral Research

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Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/β-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice.

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“…Recombinant BMP9 was also shown to be one of the most potent osteogenic inducers and a regulator of several biological functions, including chondrogenesis, glucose metabolism, neuronal differentiation, and iron balance . BMP9 was recently shown to be principally produced by hepatic stellate cells (HSCs) . BMP9 is also circulating in blood at active concentrations, mainly as a BMP9‐BMP10 heterodimer, and is known to be a vascular quiescence factor .…”

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confidence: 99%

Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis

et al. 2019

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Bone morphogenetic protein 9 (BMP9) is a circulating factor produced by hepatic stellate cells that plays a critical role in vascular quiescence through its endothelial receptor activin receptor-like kinase 1 (ALK1). Mutations in the gene encoding ALK1 cause hereditary hemorrhagic telangiectasia type 2, a rare genetic disease presenting hepatic vessel malformations. Variations of both the circulating levels and the hepatic mRNA levels of BMP9 have been recently associated with various forms of hepatic fibrosis. However, the molecular mechanism that links BMP9 with liver diseases is still unknown. Here, we report that Bmp9 gene deletion in 129/Ola mice triggers hepatic perisinusoidal fibrosis that was detectable from 15 weeks of age. An inflammatory response appeared within the same time frame as fibrosis, whereas sinusoidal vessel dilation developed later on. Proteomic and mRNA analyses of primary liver sinusoidal endothelial cells (LSECs) both revealed that the expression of the LSEC-specifying transcription factor GATA-binding protein 4 was strongly reduced in Bmp9 gene knockout (Bmp9-KO) mice as compared with wild-type mice. LSECs from Bmp9-KO mice also lost the expression of several terminal differentiation markers (Lyve1, Stab1, Stab2, Ehd3, Cd209b, eNos, Maf, Plvap). They gained CD34 expression and deposited a basal lamina, indicating that they were capillarized. Another main characteristic of differentiated LSECs is the presence of permeable fenestrae. LSECs from Bmp9-KO mice had a significantly reduced number of fenestrae. This was already observable in 2-week-old pups. Moreover, we could show that addition of BMP9 to primary cultures of LSECs prevented the loss of their fenestrae and maintained the expression levels of Gata4 and Plvap. Conclusion: Taken together, our observations show that BMP9 is a key paracrine regulator of liver homeostasis, controlling LSEC fenestration and protecting against perivascular hepatic fibrosis.

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BMP-9 interferes with liver regeneration and promotes liver fibrosis

Cited by 116 publications

References 57 publications

Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis

Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis

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