Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation

Ebisawa, Takanori; Tada, Keiichiro; Kitajima, Isao; Tojo, K.; Sampath, T. Kuber; Kawabata, Masahiro; Miyazono, Kohei; Imamura, Takeshi

doi:10.1242/jcs.112.20.3519

Cited by 276 publications

(33 citation statements)

References 41 publications

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“…Upon proteolytic cleavage, active, mature hBMP-6 is released from the degrading ECM which in turn stimulates cells to repair the lost tissue . BMP-6 is known to regulate differentiation of various cells implicated in cartilage and bone formation during skeletal development and fracture repair. − This is exemplified by the hBMP-6 mediated induction of alkaline phosphatase activity in osteoblast precursor cells, a hallmark of osteogenic differentiation …”

Section: Introductionmentioning

confidence: 92%

“…4−6 This is exemplified by the hBMP-6 mediated induction of alkaline phosphatase activity in osteoblast precursor cells, a hallmark of osteogenic differentiation. 7 Throughout the past decade, many efforts have been devoted to develop methods to immobilize GFs at biomaterial surfaces. 8−10 The main aim of these efforts is to mimic the endogenous GF delivery system and thereby improving the performance of biomaterials in tissue engineering and therapeutic applications.…”

Section: ■ Introductionmentioning

confidence: 99%

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Hydrolytically Labile Linkers Regulate Release and Activity of Human Bone Morphogenetic Protein-6

et al. 2018

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Release of growth factors while simultaneously maintaining their full biological activity over a period of days to weeks is an important issue in controlled drug delivery and in tissue engineering. In addition, the selected strategy to immobilize growth factors largely determines their biological activity. Silica surfaces derivatized with glycidyloxy propyl trimethoxysilane and poly(glycidyl methacrylate) brushes yielded epoxide-functionalized surfaces onto which human bone morphogenetic protein-6 (hBMP-6) was immobilized giving stable secondary amine bonds. The biological activity of hBMP-6 was unleashed by hydrolysis of the surface siloxane and ester bonds. We demonstrate that this type of labile bonding strategy can be applied to biomaterial surfaces with relatively simple and biocompatible chemistry, such as siloxane, ester, and imine bonds. Our data indicates that the use of differential hydrolytically labile linkers is a versatile method for functionalization of biomaterials with a variety of growth factors providing control over their biological activity.

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Section: Introductionmentioning

confidence: 92%

Section: ■ Introductionmentioning

confidence: 99%

Hydrolytically Labile Linkers Regulate Release and Activity of Human Bone Morphogenetic Protein-6

et al. 2018

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“…The specificities of BMP binding to type receptors depend on the identities of the interacting type II receptors and cell types [ 283 ] ( Figure 2 ). BMPs display a different affinity for BMP type I receptors: BMP-2 and BMP-4 bind to ALK-3 and ALK-6 [ 22 , 132 , 284 ] ( Figure 2 and Figure 5 ), while BMP-6 and BMP-7 bind strongly to ALK-2 and weakly to ALK-6 [ 285 ]. BMP-14 preferentially binds to ALK-6 [ 286 ].…”

Section: Bmp Signaling During Tooth Developmentmentioning

confidence: 99%

BMP Signaling Pathway in Dentin Development and Diseases

Liu

Goldman

MacDougall

et al. 2022

Cells

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BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described.

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“…OD16 demonstrated a stronger inhibitory effect than LDN-193189, while LDN-193189 was significantly more potent than OD29. Next, we stimulated the EA.hy926 cells with BMP6, which mainly signals via ALK2 and does not bind and signal via ALK1 [43], and interrogated the effects of LDN-193189, OD16, and OD29 on signaling mediated via ALK2. LDN-193189 and OD16 efficiently inhibited BMP6-induced SMAD1/5 phosphorylation at a low dose (0.1 µM) (Figure 2J,K).…”

Section: Od16 and Od29 Specifically Inhibit Bmp But Not Tgf-β Signalingmentioning

confidence: 99%

Inhibiting Endothelial Cell Function in Normal and Tumor Angiogenesis Using BMP Type I Receptor Macrocyclic Kinase Inhibitors

Ren

Thorikay

et al. 2021

Cancers

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Angiogenesis, i.e., the formation of new blood vessels from pre-existing endothelial cell (EC)-lined vessels, is critical for tissue development and also contributes to neovascularization-related diseases, such as cancer. Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are among many secreted cytokines that regulate EC function. While several pharmacological anti-angiogenic agents have reached the clinic, further improvement is needed to increase clinical efficacy and to overcome acquired therapy resistance. More insights into the functional consequences of targeting specific pathways that modulate blood vessel formation may lead to new therapeutic approaches. Here, we synthesized and identified two macrocyclic small molecular compounds termed OD16 and OD29 that inhibit BMP type I receptor (BMPRI)-induced SMAD1/5 phosphorylation and downstream gene expression in ECs. Of note, OD16 and OD29 demonstrated higher specificity against BMPRI activin receptor-like kinase 1/2 (ALK1/2) than the commonly used small molecule BMPRI kinase inhibitor LDN-193189. OD29, but not OD16, also potently inhibited VEGF-induced extracellular regulated kinase MAP kinase phosphorylation in ECs. In vitro, OD16 and OD29 exerted strong inhibition of BMP9 and VEGF-induced ECs migration, invasion and cord formation. Using Tg (fli:EGFP) zebrafish embryos, we found that OD16 and OD29 potently antagonized dorsal longitudinal anastomotic vessel (DLAV), intra segmental vessel (ISV), and subintestinal vessel (SIV) formation during embryonic development. Moreover, the MDA-MB-231 breast cancer cell-induced tumor angiogenesis in zebrafish embryos was significantly decreased by OD16 and OD29. Both macrocyclic compounds might provide a steppingstone for the development of novel anti-angiogenesis therapeutic agents.

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Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation

Cited by 276 publications

References 41 publications

Hydrolytically Labile Linkers Regulate Release and Activity of Human Bone Morphogenetic Protein-6

Hydrolytically Labile Linkers Regulate Release and Activity of Human Bone Morphogenetic Protein-6

BMP Signaling Pathway in Dentin Development and Diseases

Inhibiting Endothelial Cell Function in Normal and Tumor Angiogenesis Using BMP Type I Receptor Macrocyclic Kinase Inhibitors

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