Immunohistochemical analysis revealed the expression of bone morphogenetic proteins-4, 6, 7, and 9 in human induced membrane samples treated with the Masquelet technique

Background Induced membrane (IM) is the key component of Masquelet reconstruction surgery for the treatment of bone defects. IM is formed around the cement spacer and is known to secrete growth factors and osteoinductive factors. However, there is limited evidence available concerning the presence of osteoinductive factors in IM. This study aimed to investigate the existence of bone morphogenetic proteins (BMPs) in IM harvested from patients during the treatment of bone defects using the Masquelet technique. Methods This study involved six patients whose bone defects had been treated using the Masquelet technique. The affected sites were the femur (n = 3) and the tibia (n = 3). During the second-stage surgery, 1 cm2 pieces of IM were harvested. Histological sections of IM were immunostained with anti-BMP-4, 6, 7, and 9 antibodies. Human bone tissue served as the positive control. Results The presence of BMP-4, 6, 7, and 9 was observed in all IM samples. Further, immunolocalization of BMP-4, 6, 7, and 9 was observed in blood vessels and fibroblasts in all IM samples. Immunolocalization of BMP-4, 6, 7, and 9 was also observed in bone tissue within the IM in one sample, in which osteogenesis inside the IM was observed. Conclusions This study showed that osteoinductive factors BMP-4, 6, 7, and 9 were present in the IM harvested from patients, providing evidence indicating that the Masquelet technique effectively contributes to healing large bone defects. Therefore, it may be possible for surgeons to omit the addition of BMPs to bone grafts, given the endogenous secretion of BMPs from the IM.

Altered BMP2/4 Signaling in Stem Cells and Their Niche: Different Cancers but Similar Mechanisms, the Example of Myeloid Leukemia and Breast Cancer

Understanding mechanisms of cancer development is mandatory for disease prevention and management. In healthy tissue, the microenvironment or niche governs stem cell fate by regulating the availability of soluble molecules, cell-cell contacts, cell-matrix interactions, and physical constraints. Gaining insight into the biology of the stem cell microenvironment is of utmost importance, since it plays a role at all stages of tumorigenesis, from (stem) cell transformation to tumor escape. In this context, BMPs (Bone Morphogenetic Proteins), are key mediators of stem cell regulation in both embryonic and adult organs such as hematopoietic, neural and epithelial tissues. BMPs directly regulate the niche and stem cells residing within. Among them, BMP2 and BMP4 emerged as master regulators of normal and tumorigenic processes. Recently, a number of studies unraveled important mechanisms that sustain cell transformation related to dysregulations of the BMP pathway in stem cells and their niche (including exposure to pollutants such as bisphenols). Furthermore, a direct link between BMP2/BMP4 binding to BMP type 1 receptors and the emergence and expansion of cancer stem cells was unveiled. In addition, a chronic exposure of normal stem cells to abnormal BMP signals contributes to the emergence of cancer stem cells, or to disease progression independently of the initial transforming event. In this review, we will illustrate how the regulation of stem cells and their microenvironment becomes dysfunctional in cancer via the hijacking of BMP signaling with main examples in myeloid leukemia and breast cancers.

Role of bone morphogenetic proteins in periodontal tissue engineering: Relatively unexplored horizon

Tissue engineering aims to reconstruct the natural target tissue by a combination of three key elements stem/progenitor cells (that will create the new tissue), signaling molecules (that instruct the cells to form the desired tissue) scaffold/extracellular matrix (to hold the cells). Regeneration of the periodontal tissues following destructive episodes of various forms of periodontitis is a formidable challenge to periodontologists. Bone morphogenic proteins have been considered as the most potent growth factors that can promote the bone regeneration. This review will emphasize on the unique nature of the tissue engineered bone morphogenic proteins molecules regarding their structure, classification, signaling mechanism, etc. which will further help in understanding their role and potential advances necessary to facilitate the process of regeneration in the field of periodontics.

Quantitative Imaging in Whole-mount Zebrafish Embryos Traces Morphogen Gradient Maintenance and Noise Propagation in BMP Signaling

Dorsoventral (DV) embryonic patterning relies on precisely controlled interpretation of morphogen signaling. In all vertebrates, DV axis specification is informed by gradients of bone morphogenetic proteins (BMPs). We developed a 3D single-molecule mRNA quantification method in whole-mount zebrafish to quantify the inputs and outputs in this pathway. In combination with 3D computational modeling of zebrafish embryo development, data from this method revealed that sizzled (Szl), shaped by BMP and Nodal signaling, maintained a consistent inhibition level with chordin (Chd) to maintain the BMP morphogen gradient. Intriguingly, intrinsic BMP morphogen expression is highly noisy at the ventral marginal layer in the early zebrafish gastrula, where the gradient for DV patterning is established, which implies an unexpected role for noise in gradient shaping.

Regulation of the Immune System in Health and Disease by Members of the Bone Morphogenetic Protein Family

Bone morphogenetic proteins (BMPs) are potent signaling molecules initially described as osteopromoting proteins. BMPs represent one of the members of the larger TGFβ family and today are recognized for their important role in numerous processes. Among the wide array of functions recently attributed to them, BMPs were also described to be involved in the regulation of components of the innate and adaptive immune response. This review focuses on the signaling pathway of BMPs and highlights the effects of BMP signaling on the differentiation, activation, and function of the main cell types of the immune system.

Differentiation of adipose-derived stem cells to chondrocytes using electrospraying

An important challenge in the fabrication of tissue engineered constructs for regenerative medical applications is the development of processes capable of delivering cells and biomaterials to specific locations in a consistent manner. Electrospraying live cells has been introduced in recent years as a cell seeding method, but its effect on phenotype nor genotype has not been explored. A promising candidate for the cellular component of these constructs are human adipose-derived stem cells (hASCs), which are multipotent stem cells that can be differentiated into fat, bone, and cartilage cells. They can be easily and safely obtained from adipose tissue, regardless of the age and sex of the donor. Moreover, these cells can be maintained and expanded in culture for long periods of time without losing their differentiation capacity. In this study, hASCs directly incorporated into a polymer solution were electrosprayed, inducing differentiation into chondrocytes, without the addition of any exogenous factors. Multiple studies have demonstrated the effects of exposing hASCs to biomolecules—such as soluble growth factors, chemokines, and morphogens—to induce chondrogenesis. Transforming growth factors (e.g., TGF-β) and bone morphogenetic proteins are particularly known to play essential roles in the induction of chondrogenesis. Although growth factors have great therapeutic potential for cell-based cartilage regeneration, these growth factor-based therapies have presented several clinical complications, including high dose requirements, low half-life, protein instability, higher costs, and adverse effects in vivo. The present data suggests that electrospraying has great potential as hASCs-based therapy for cartilage regeneration.

Bioactive molecules for regenerative pulp capping

Since the discovery of bioactive molecules sequestered in dentine, researchers have been exploring ways to harness their activities for dental regeneration. One specific area, discussed in this review, is that of dental-pulp capping. Dental-pulp caps are placed when the dental pulp is exposed due to decay or trauma in an attempt to enhance tertiary dentine deposition. Several materials are used for dental-pulp capping; however, natural biomimetic scaffolds may offer advantages over manufactured materials such as improved aesthetic, biocompatibility and success rate. The present review discusses and appraises the current evidence surrounding biomimetic dental-pulp capping, with a focus on bioactive molecules sequestered in dentine. Molecules covered most extensively in the literature include transforming growth factors (TGF-βs, specifically TGF-β1) and bone morphogenetic proteins (BMPs, specifically BMP-2 and BMP-7). Further studies would need to explore the synergistic use of multiple peptides together with the development of a tailored scaffold carrier. The roles of some of the molecules identified in dentine need to be explored before they can be considered as potential bioactive molecules in a biomimetic scaffold for dental-pulp capping. Future in vivo work needs to consider the inflammatory environment of the dental pulp in pulpal exposures and compare pulp-capping materials.

Effect of Dorsomorphin Homolog 1 (DMH1) against Diabetic Dyslipidemia in Streptozotocin-induced Diabetic Rats

Dyslipidemia is usually observed in both types of diabetes and, particularly, “atherogenic dyslipidemic triad” is strongly linked to a higher risk of adverse cardiovascular outcome. On the other hand, bone morphogenetic proteins (BMP) are a group of wide variety of proteins which were found overexpressed and implicated in contribution and acceleration of atherosclerotic calcification. So, the present study aimed to assess effect of DMH1, a selective BMP inhibitor, in a rat model of diabetic-induced dyslipidemia. Methods: STZ-induced diabetes in Wistar rats was used as a model to assess the antihyperlipidemic effect of DMH1(5mg/kg) for a period of 8 weeks. Rats were divided intonormal control (C=10), diabetic control (DC=10), diabetic+vehicle (DV=10) and diabetic DMH1-treated rats (DT=10). Fasting blood glucose (FBG) level was measured on weekly bases. Then, at the end of the experiment, rats were anesthetized and blood samples were collected for the determination of total cholesterol (TC), triglyceride (TG), LDL and HDL levels using the appropriate ELISA assay. Results: FBG levels for all diabetic groups were significantly high, during the experiment period, compared to the control (P< 0.001). While dyslipidemia was remarkable in the diabetic non-treated groups, DMH1 treatment showed a significant decrease in TC (P< 0.001), TG (P< 0.05) and LDL levels (P< 0.001) compared to the non-treated groups (DC & DV). Concurrently, HDL levels for DT group were significantly increased compared to DC or DV groups (P< 0.01). Conclusion: The present experiment showed that DMH1 possessed encouraging activityagainst dyslipidemia in STZ-induced diabetic rats. Our results are promoting for more interest and investigation regarding antihyperlipidemic effect of DMH1 and BMP/Smad pathway in further experimental studies.

Quantitative imaging in whole-mount zebrafish embryos traces morphogen gradient maintenance and noise propagation in BMP signaling

Dorsoventral (DV) embryonic patterning relies on precisely controlled interpretation of morphogen signaling. In all vertebrates, DV axis specification is informed by gradients of Bone Morphogenetic Proteins (BMPs). We developed a 3D single-molecule mRNA quantification method in whole-mount zebrafish to quantify the inputs and outputs in this pathway. In combination with 3D computational modeling of zebrafish embryo development, data from this method revealed that Sizzled (Szl), shaped by BMP and Nodal signaling, kept a consistent inhibition level with Chordin (Chd) to maintain the BMP morphogen gradient. Intriguingly, BMP morphogen intrinsic expression is highly noisy at the ventral marginal layer in early zebrafish gastrula, where the gradient for DV patterning is established, which implies an unexpected role for noise in gradient shaping.

The Role of BMP Signaling in Female Reproductive System Development and Function

Bone morphogenetic proteins (BMPs) are a group of multifunctional growth factors that belong to the transforming growth factor-β (TGF-β) superfamily of proteins. Originally identified by their ability to induce bone formation, they are now known as essential signaling molecules that regulate the development and function of the female reproductive system (FRS). Several BMPs play key roles in aspects of reproductive system development. BMPs have also been described to be involved in the differentiation of human pluripotent stem cells (hPSCs) into reproductive system tissues or organoids. The role of BMPs in the reproductive system is still poorly understood and the use of FRS tissue or organoids generated from hPSCs would provide a powerful tool for the study of FRS development and the generation of new therapeutic perspectives for the treatment of FRS diseases. Therefore, the aim of this review is to summarize the current knowledge about BMP signaling in FRS development and function.