BMP-9 Induced Osteogenic Differentiation of Mesenchymal Stem Cells: Molecular Mechanism and Therapeutic Potential

Luther, Gaurav; Wagner, Eric R.; Zhu, Guoqiang; Kang, Qi; Luo, Qing; Lamplot, Joseph D.; Bi, Yang; Luο, Xingguang; Luo, Jinyong; Teven, Chad M.; Shi, Qiong; Kim, Stephanie H.; Gao, Jian‐Li; Huang, Enyi; Yang, Ke; Rames, Richard; Liu, Xing; Li, Mi; Hu, Ning; Liu, Hong; Su, Yuxi; Chen, Liang; He, Bai‐Cheng; Zuo, Guo‐Wei; Deng, Zhong‐Liang; Reid, Russell R.; Luu, Hue H.; Haydon, Rex C.; He, Tong‐Chuan

doi:10.2174/156652311795684777

Cited by 149 publications

(180 citation statements)

References 145 publications

(249 reference statements)

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“…Our previous studies have revealed that BMP9 is one of the most osteogenic factors for inducing osteoblastic differentiation in MSCs Deng et al, 2008;Kang et al, 2004;Luther et al, 2011;Luu et al, 2007). However, the molecular mechanisms underlying BMP9 functions in MSCs remain to be fully elucidated.…”

Section: Hif1a Is Upregulated In Bmp9-stimulated Mscsmentioning

confidence: 99%

“…We have found that BMP9 is one of the most potent BMPs among the 14 types of BMPs in inducing osteogenic differentiation of MSCs both in vitro and in vivo by regulating several important downstream targets during BMP9-induced osteoblast differentiation Kang et al, 2004;Luo et al, 2004;Luther et al, 2011;Luu et al, 2007;Peng et al, 2003;Peng et al, 2004;Sharff et al, 2009;Tang et al, 2009). BMP9 (also known as growth differentiation factor 2, or GDF-2) was identified in the developing mouse liver (Song et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

Jiang

Huang

et al. 2013

Journal of Cell Science

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SummaryMesenchymal stromal progenitor cells (MSCs) are multipotent progenitors that can be isolated from numerous tissues. MSCs can undergo osteogenic differentiation under proper stimuli. We have recently demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most osteogenic BMPs. As one of the least studied BMPs, BMP9 has been shown to regulate angiogenesis in endothelial cells. However, it is unclear whether BMP9-regulated angiogenic signaling plays any important role in the BMP9-initiated osteogenic pathway in MSCs. Here, we investigate the functional role of hypoxia-inducible factor 1a (HIF1a)-mediated angiogenic signaling in BMP9-regulated osteogenic differentiation of MSCs. We find that BMP9 induces HIF1a expression in MSCs through Smad1/5/8 signaling. Exogenous expression of HIF1a potentiates BMP9-induced osteogenic differentiation of MSCs both in vitro and in vivo. siRNA-mediated silencing of HIF1a or HIF1a inhibitor CAY10585 profoundly blunts BMP9-induced osteogenic signaling in MSCs. HIF1a expression regulated by cobalt-induced hypoxia also recapitulates the synergistic effect between HIF1a and BMP9 in osteogenic differentiation. Mechanistically, HIF1a is shown to exert its synergistic effect with BMP9 by inducing both angiogenic signaling and osteogenic signaling in MSCs. Thus, our findings should not only expand our understanding of the molecular basis behind BMP9-regulated osteoblastic lineage-specific differentiation, but also provide an opportunity to harness the BMP9-induced synergy between osteogenic and angiogenic signaling pathways in regenerative medicine.

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Section: Hif1a Is Upregulated In Bmp9-stimulated Mscsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

Jiang

Huang

et al. 2013

Journal of Cell Science

Self Cite

110

112

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“…BMP9 has emerged as a powerful growth factor currently at the forefront of bone healing technologies (36) and as a therapeutic target in neurodegenerative disease (37) and cancer (38). Administration of BMP9 holds therapeutic potential in bone and cartilage defects and neurodegenerative disease (36,37).…”

Section: Discussionmentioning

confidence: 99%

“…Administration of BMP9 holds therapeutic potential in bone and cartilage defects and neurodegenerative disease (36,37). In addition, targeting BMP9/BMP10 signaling by soluble Alk1-Fc and an ALK1 blocking antibody is explored in cancer treatment (23,38).…”

Section: Discussionmentioning

confidence: 99%

Rapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains

Kienast

Jucknischke

Scheiblich

et al. 2016

Journal of Biological Chemistry

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By non-covalent association after proteolytic cleavage, the pro-domains modulate the activities of the mature growth factor domains across the transforming growth factor-␤ family. In the case of bone morphogenic protein 9 (BMP9), however, the pro-domains do not inhibit the bioactivity of the growth factor, and the BMP9⅐pro-domain complexes have equivalent biological activities as the BMP9 mature ligand dimers. By using realtime surface plasmon resonance, we could demonstrate that either binding of pro-domain-complexed BMP9 to type I receptor activin receptor-like kinase 1 (ALK1), type II receptors, coreceptor endoglin, or to mature BMP9 domain targeting antibodies leads to immediate and complete displacement of the pro-domains from the complex. Vice versa, pro-domain binding by an anti-pro-domain antibody results in release of the mature BMP9 growth factor. Based on these findings, we adjusted ELISA assays to measure the protein levels of different BMP9 variants. Although mature BMP9 and inactive precursor BMP9 protein were directly detectable by ELISA, BMP9⅐pro-domain complex could only be measured indirectly as dissociated fragments due to displacement of mature growth factor and prodomains after antibody binding. Our studies provide a model in which BMP9 can be readily activated upon getting into contact with its receptors. This increases the understanding of the underlying biology of BMP9 activation and also provides guidance for ELISA development for the detection of circulating BMP9 variants.Bone morphogenic protein 9 (BMP9 2 ; also known as growth and differentiation factor 2 (GDF2)), is a member of the transforming growth factor ␤ (TGF␤) superfamily. BMP9 is constitutively expressed in liver and secreted into the circulation at active concentrations (1). Circulating BMP9 is a potent biological effector signaling through type I receptor activin-receptorlike kinase 1 (ALK1) in endothelial cells, thereby maintaining vascular homeostasis (2, 3). BMP9 and ALK1 are required for properly organized blood and lymphatic vascular development (4 -6). Human mutations in ALK1 lead to a genetic vascular disorder known as hereditary hemorrhagic telangiectasia (7). Recently, mutations in BMP9 have been identified in individuals with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia (8). BMP9 was also discovered to function as a neurotropic factor, potently inducing and maintaining the cholinergic phenotype in the central nervous system (9), and is also the most potent BMP for inducing osteogenic, and to a lesser extent adipogenic and chondrogenic differentiation (10, 11). Osteogenic signaling requires both ALK1 and the low affinity type I receptor ALK2 (12). Type II receptors activin receptor IIA and IIB (ActRIIA and ActRIIB) and BMP receptor II (BMPRII) have also been implicated in ALK1/BMP9 signaling (13). Moreover, endoglin (ENG) has been identified as a co-receptor that can increase BMP9/ALK1 signaling (3,14). This is reflected in a model where ENG and ALK1 act together to bind...

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“…They can differentiate into muscle cells, bone cells, or cartilage cells (Luther et al, 2011). MSCs are often used as seed cells in the bone cell regeneration therapy for fracture trauma repair (Li et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect of BMP9 and TGF-β in the proliferation and differentiation of osteoblasts

Li¹,

Liu²,

Ma³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We investigated the synergistic effect of bone morphogenetic protein 9 (BMP9) and transforming growth factor (TGF)-b in the transformation of mesenchymal stem cells into osteoblasts. We evaluated the effect of BMP9 and TGF-b on the induction of osteoblast formation. Mitogen-activated protein kinase (MAPK) pathway-related proteins such as p38, extracellular receptor kinase 1/2, and c-Jun N-terminal kinase (JNK) were analyzed. The interactions between TGF-Smad and BMP-MAPK were also studied. BMP9 alone induced the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and enhanced phosphorylation of p38, extracellular receptor kinase 1/2, and JNK. TGF-b alone failed to induce transformation, but could increase the effect of X.L. Li et al. 7606©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (3): 7605-7615 (2015) BMP9. In this process the activation of Smad resulted in activation of the JNK pathway in the MAPK pathway. BMP9 induced osteogenesis of MSC differentiation through the MAKP pathway, while TGF-b contributed to BMP9 enhancement through the Smad-JNK pathway.

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BMP-9 Induced Osteogenic Differentiation of Mesenchymal Stem Cells: Molecular Mechanism and Therapeutic Potential

Cited by 149 publications

References 145 publications

BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

Rapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains

Synergistic effect of BMP9 and TGF-β in the proliferation and differentiation of osteoblasts

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