BMP2/7 heterodimer enhances osteogenic differentiation of rat BMSCs via ERK signaling compared with respective homodimers

Miao, Chunlei; Qin, Dengke; Cao, Peigang; Lu, Ping Hung; Xia, Yu-Tong; Li, Mengjiao; Sun, Mingzhong; Zhang, Wei; Yang, Fanghong; Zhang, Yingjie; Tang, Shengjian; Liu, Tianyi; Liu, Fangjun

doi:10.1002/jcb.28162

Cited by 14 publications

(14 citation statements)

References 32 publications

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“…A number of studies have investigated also other heterodimeric BMPs, mostly BMP2/6, BMP2/7, and BMP4/7, which were recombinantly produced and purified from co-expression in eukaryotic cell culture or from expression in bacteria and subsequent refolding [142,143,148]. A common observation of these studies was the strongly increased activity of the heterodimeric BMP proteins (i.e., lower half-maximal effective concentrations required to observe similar transcription levels of marker genes) compared to their homodimeric paralogues [143,[148][149][150][151][152][153]. Different mechanisms were proposed to explain how these increased bioactivities might be exerted.…”

Section: Heterodimeric Ligands-an Unexplored Worldmentioning

confidence: 99%

Specification of BMP Signaling

Nickel

Mueller

2019

Cells

109

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Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.

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Section: Heterodimeric Ligands-an Unexplored Worldmentioning

confidence: 99%

Specification of BMP Signaling

Nickel

Mueller

2019

Cells

109

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“…Bone morphogenic protein 2 (BMP2) is one of the most osteoinductive growth factors and has been approved by the US Food and Drug Administration (FDA) for clinical use in the stimulation of osteogenic differentiation of BMSCs [ 22 ]. Despite promising results, the application of BMP2 in clinical settings requires high doses, which are associated with severe side effects, including ectopic bone formation, immunological reactions, and tumorigenesis [ [23] , [24] , [25] ]. The low efficacy of BMP2 is attributed to two characteristics: firstly, the limited availability of endogenous mesenchymal cells at the site of large bone defects, and secondly, the short half-life of BMP2.…”

Section: Introductionmentioning

confidence: 99%

In situ bone regeneration with sequential delivery of aptamer and BMP2 from an ECM-based scaffold fabricated by cryogenic free-form extrusion

Sun

Meng

Ding

et al. 2021

Bioactive Materials

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In situ tissue engineering is a powerful strategy for the treatment of bone defects. It could overcome the limitations of traditional bone tissue engineering, which typically involves extensive cell expansion steps, low cell survival rates upon transplantation, and a risk of immuno-rejection. Here, a porous scaffold polycaprolactone (PCL)/decellularized small intestine submucosa (SIS) was fabricated via cryogenic free-form extrusion, followed by surface modification with aptamer and PlGF-2 123-144 *-fused BMP2 (pBMP2). The two bioactive molecules were delivered sequentially. The aptamer Apt19s, which exhibited binding affinity to bone marrow-derived mesenchymal stem cells (BMSCs), was quickly released, facilitating the mobilization and recruitment of host BMSCs. BMP2 fused with a PlGF-2 123-144 peptide, which showed “super-affinity” to the ECM matrix, was released in a slow and sustained manner, inducing BMSC osteogenic differentiation. In vitro results showed that the sequential release of PCL/SIS-pBMP2-Apt19s promoted cell migration, proliferation, alkaline phosphatase activity, and mRNA expression of osteogenesis-related genes. The in vivo results demonstrated that the sequential release system of PCL/SIS-pBMP2-Apt19s evidently increased bone formation in rat calvarial critical-sized defects compared to the sequential release system of PCL/SIS-BMP2-Apt19s. Thus, the novel delivery system shows potential as an ideal alternative for achieving cell-free scaffold-based bone regeneration in situ .

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“…BMP7 is a cartilage repair factor enhancing anabolic and reducing catabolic responses in cartilage and the IVD [14]. Noteworthy, BMP heterodimers were suggested to be more potent than homodimers, not only in bone formation [15][16][17][18][19], but also in NP regeneration [20]. However, it is not clear whether these effects require a heterodimeric conformation, or can be achieved by costimulation by combinations of the separate homodimers, as this was only once taken as a comparator, in ectopic bone formation [15].…”

Section: Introductionmentioning

confidence: 99%

Bone Morphogenetic Proteins for Nucleus Pulposus Regeneration

Krouwels

Iljas

Kragten

et al. 2020

IJMS

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Matrix production by nucleus pulposus (NP) cells, the cells residing in the center of the intervertebral disc, can be stimulated by growth factors. Bone morphogenetic proteins (BMPs) hold great promise. Although BMP2 and BMP7 have been used most frequently, other BMPs have also shown potential for NP regeneration. Heterodimers may be more potent than single homodimers, but it is not known whether combinations of homodimers would perform equally well. In this study, we compared BMP2, BMP4, BMP6, and BMP7, their combinations and heterodimers, for regeneration by human NP cells. The BMPs investigated induced variable matrix deposition by NP cells. BMP4 was the most potent, both in the final neotissue glysosaminoglycan content and incorporation efficiency. Heterodimers BMP2/6H and BMP2/7H were more potent than their respective homodimer combinations, but not the BMP4/7H heterodimer. The current results indicate that BMP4 might have a high potential for regeneration of the intervertebral disc. Moreover, the added value of BMP heterodimers over their respective homodimer BMP combinations depends on the BMP combination applied.

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BMP2/7 heterodimer enhances osteogenic differentiation of rat BMSCs via ERK signaling compared with respective homodimers

Cited by 14 publications

References 32 publications

Specification of BMP Signaling

Specification of BMP Signaling

In situ bone regeneration with sequential delivery of aptamer and BMP2 from an ECM-based scaffold fabricated by cryogenic free-form extrusion

Bone Morphogenetic Proteins for Nucleus Pulposus Regeneration

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