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Review
. 2024 Aug 15;14(8):1013.
doi: 10.3390/biom14081013.

Unveiling the Impact of BMP9 in Liver Diseases: Insights into Pathogenesis and Therapeutic Potential

Han Chen  1   2 , Ying-Yi Li  3 , Kouki Nio  3 , Hong Tang  1   2
Affiliations
Review

Unveiling the Impact of BMP9 in Liver Diseases: Insights into Pathogenesis and Therapeutic Potential

Han Chen et al. Biomolecules. .

Abstract

Bone morphogenetic proteins (BMPs) are a group of growth factors belonging to the transforming growth factor β(TGF-β) family. While initially recognized for their role in bone formation, BMPs have emerged as significant players in liver diseases. Among BMPs with various physiological activities, this comprehensive review aims to delve into the involvement of BMP9 specifically in liver diseases and provide insights into the complex BMP signaling pathway. Through an enhanced understanding of BMP9, we anticipate the discovery of new therapeutic options and potential strategies for managing liver diseases.

Keywords: BMP signaling; BMP9; liver cancer; liver disease; liver fibrosis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
BMP proteins and receptors. The summary of BMP family members and their alternative names, type I and type II receptors, and Co-Smads. OP, osteogenic protein; Vgr, vegetal related; RAI, atrial isomerism right; KFS3, Klippel-Feil syndrome 3, autosomal dominant; ALK, anaplastic lymphoma kinase; BMPRIA, bone morphogenetic protein receptor IA; BMPRIB, bone morphogenetic protein receptor IB; ACVR1, Activin A receptor, type I.
Figure 2
Figure 2
Synthesis procedure for BMP9. BMP9 is synthesized as a 429 amino acid (aa) precursor protein known as pre–pro-BMP9. It consists of a 22 aa signal peptide, a 297 aa prodomain, and a 110 aa mature protein. After synthesis, the pre-pro-BMP9 undergoes homodimerization and subsequent cleavage, resulting in two active forms: the short mature BMP9 (25 kDa) and the complexed form (100 kDa). The short mature BMP9 (25 kDa) includes two forms of dimers, with (D-form) or without (M-form) an intermolecular disulfide bond. Within circulating BMP9, the inactive unprocessed pro-BMP9 accounts for 40%, while the active complexed form accounts for 60%.
Figure 3
Figure 3
Diagram of TGF-β and BMP9 signaling pathways. BMP9 binds to heterotetrameric receptor complexes (ALK1/ALK2 and BMPR-II/ActR-IIA/ActR-IIB), resulting in the phosphorylation of downstream Smad1/5/8 (pSmad1/5/8). pSmad1/5/8 subsequently interacts with Smad4, translocates into the nucleus, and binds to the promoters of _target genes, thereby promoting gene expression. The co-receptor endoglin plays a crucial role in activating the BMP9—pSmad1/5/8 pathway. Similarly, TGF-β binds to heterotetrameric receptor complexes (ALK5 and TGFBR2), leading to the phosphorylation of downstream Smad2/3 (pSmad2/3). pSmad2/3 then interacts with Smad4, translocates into the nucleus, and binds to the promoters of _target genes, thereby promoting gene expression. pSmad1/5/8 are negative regulators of Smad3-dependent gene transcription. Smad6 and Smad7 inhibit the phosphorylation of Smad1/5/8 and Smad2/3.
Figure 4
Figure 4
Smad-dependent pathway and non-Smad pathways.
Figure 5
Figure 5
Schematic diagram of the effects of BMP9 on liver diseases.
See this image and copyright information in PMC

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