BMPs in bone regeneration: Less is more effective, a paradigm-shift

Schmidt‐Bleek, Katharina; Willie, Bettina M.; Schwabe, Philipp; Seemann, Petra; Duda, Georg N.

doi:10.1016/j.cytogfr.2015.11.006

Cited by 91 publications

(76 citation statements)

References 65 publications

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“…The involvement of BMP/GDF signaling pathways in a wide range of developmental and pathophysiological processes of reproductive biology makes targeting these pathways a potential therapeutic approach to overcome female infertility. At present, several recombinant human BMPs/GDFs and their inhibitors or antagonists have undergone clinical trials or have received US Food and Drug Administration (FDA) approval in human skeletal and muscular systems (Gautschi et al ., 2007; Kinouchi et al ., 2008; Lissenberg-Thunnissen et al ., 2011; Smith and Lin, 2013; Lee and Wikesjo, 2014; Schmidt-Bleek et al ., 2016). Furthermore, the latest development of gene therapy and BMP-ligand trapping approaches are currently attracting more attention (Kinouchi et al ., 2008; Hawinkels et al ., 2013; Sherman et al ., 2013; Spiekerkoetter et al ., 2013).…”

Section: Perspectives and Therapeutic Potentialmentioning

confidence: 99%

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Chang

Qiao

Leung

2016

Hum. Reprod. Update

225

207

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BACKGROUNDInitially identified for their capability to induce heterotopic bone formation, bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor β superfamily. Using cellular and molecular genetic approaches, recent studies have implicated intra-ovarian BMPs as potent regulators of ovarian follicular function. The bi-directional communication of oocytes and the surrounding somatic cells is mandatory for normal follicle development and oocyte maturation. This review summarizes the current knowledge on the physiological role and molecular determinants of these ovarian regulatory factors within the human germline-somatic regulatory loop.OBJECTIVE AND RATIONALEThe regulation of ovarian function remains poorly characterized in humans because, while the fundamental process of follicular development and oocyte maturation is highly similar across species, most information on the regulation of ovarian function is obtained from studies using rodent models. Thus, this review focuses on the studies that used human biological materials to gain knowledge about human ovarian biology and disorders and to develop strategies for preventing, diagnosing and treating these abnormalities.SEARCH METHODSRelevant English-language publications describing the roles of BMPs or growth differentiation factors (GDFs) in human ovarian biology and phenotypes were comprehensively searched using PubMed and the Google Scholar database. The publications included those published since the initial identification of BMPs in the mammalian ovary in 1999 through July 2016.OUTCOMESStudies using human biological materials have revealed the expression of BMPs, GDFs and their putative receptors as well as their molecular signaling in the fundamental cells (oocyte, cumulus/granulosa cells (GCs) and theca/stroma cells) of the ovarian follicles throughout follicle development. With the availability of recombinant human BMPs/GDFs and the development of immortalized human cell lines, functional studies have demonstrated the physiological role of intra-ovarian BMPs/GDFs in all aspects of ovarian functions, from follicle development to steroidogenesis, cell–cell communication, oocyte maturation, ovulation and luteal function. Furthermore, there is crosstalk between these potent ovarian regulators and the endocrine signaling system. Dysregulation or naturally occurring mutations within the BMP system may lead to several female reproductive diseases. The latest development of recombinant BMPs, synthetic BMP inhibitors, gene therapy and tools for BMP-ligand sequestration has made the BMP pathway a potential therapeutic target in certain human fertility disorders; however, further clinical trials are needed. Recent studies have indicated that GDF8 is an intra-ovarian factor that may play a novel role in regulating ovarian functions in the human ovary.WIDER IMPLICATIONSIntra-ovarian BMPs/GDFs are critical regulators of folliculogenesis and human ovarian functions. Any dysregulation or variations in these ligand...

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Section: Perspectives and Therapeutic Potentialmentioning

confidence: 99%

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Chang

Qiao

Leung

2016

Hum. Reprod. Update

225

207

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“…BMPs have a broad spectrum of biological functions, such as the regulation of cell proliferation and differentiation during development (21–23). In addition, some BMPs have been used in bone tissue engineering for various bone-associated diseases (24–26). Yet, the mechanism underlying these processes remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling

Cao

Wei

Lian

et al. 2017

International Journal of Molecular Medicine

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Notch is an important pathway in that it regulates cell-to-cell signal transduction, which plays an essential role in skeletal remodeling. Bone morphogenetic protein (BMP)9 has been regarded as one of the most efficient BMPs by which to induce osteogenic differentiation in mesenchymal stem cells (MSCs). Understanding the interaction between Notch and BMP9 signaling is a critical issue for optimizing the application of MSCs and BMPs in bone tissue engineering. In the present study, we investigated the role of Notch signaling in the BMP9-induced osteogenic differentiation of MSCs. Our data demonstrated that Notch signaling obviously enhanced BMP9-induced osteogenic differentiation in MSCs in vitro and in vivo. Notch signaling augmented the activity of BMP9-induced BMP/Smad signaling and increased the gene expression of essential osteogenic factors induced by BMP9 in MSCs, such as runt-related transcription factor 2 (Runx2), type I collagen (Colla1) and inhibitor of differentiation (Id)1. We also found that Notch signaling promoted the expression of activin-like kinase 2 (ALK2) induced by BMP9, and the inhibitory effect of dnALK2 on BMP9-induced osteogenic differentiation was rescued by constitutive overexpression of Delta-like 1 (DLL1). Notch signaling also exhibited an apparent effect on the proliferation of mouse embryo fibroblasts (MEFs) during BMP9-induced osteogenic differentiation. These results indicate that Notch plays a significant role in mediating BMP9-induced osteogenic differentiation in MSCs, which may be partly regulated by upregulation of the expression of ALK2.

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“…The potential of growth factor BMP-2 incorporation to promote cellular activity and enhance tissue regeneration in the context of large bone defects has been shown not only in a clinic setting (Schmidt-Bleek et al, 2016), but also using computer modeling techniques (Ribeiro et al, 2015). Ribeiro et al collected quantitative experimental data from the literature on the effect of BMP-2 on cellular activity (proliferation, migration, differentiation, extracellular matrix production, etc.)…”

Section: The Role Of Intrinsic and Extrinsic Growth Factors On Cellulmentioning

confidence: 99%

Multiscale Modeling of Bone Healing: Toward a Systems Biology Approach

2017

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Bone is a living part of the body that can, in most situations, heal itself after fracture. However, in some situations, healing may fail. Compromised conditions, such as large bone defects, aging, immuno-deficiency, or genetic disorders, might lead to delayed or non-unions. Treatment strategies for those conditions remain a clinical challenge, emphasizing the need to better understand the mechanisms behind endogenous bone regeneration. Bone healing is a complex process that involves the coordination of multiple events at different length and time scales. Computer models have been able to provide great insights into the interactions occurring within and across the different scales (organ, tissue, cellular, intracellular) using different modeling approaches [partial differential equations (PDEs), agent-based models, and finite element techniques]. In this review, we summarize the latest advances in computer models of bone healing with a focus on multiscale approaches and how they have contributed to understand the emergence of tissue formation patterns as a result of processes taking place at the lower length scales.

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BMPs in bone regeneration: Less is more effective, a paradigm-shift

Cited by 91 publications

References 65 publications

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling

Multiscale Modeling of Bone Healing: Toward a Systems Biology Approach

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