Oestrogen Represses Noggin Expression by Interfering With BMP/Smad Signalling in ER Positive Breast Cancer.

BACKGROUND/AIM: As an antagonist of bone morphogenetic protein (BMP), Noggin facilitates osteolytic bone metastases from breast cancer. The present study aimed to further dissect its role in oestrogen receptor (ER) positive breast cancer. MATERIALS AND METHODS: Noggin expression in ER positive breast cancer cell lines (MCF-7 and T-47D) was determined under conditions of oestrogen deprivation and treatment with 17-ß-oestradiol (E2). Activation of Smad1/5/8 in the oestrogen-regulated Noggin was examined using recombinant human BMP7 (rhBMP7) and a BMP receptor inhibitor (LDN-193189). The influence of Noggin on cellular functions was evaluated in MCF-7 and T-47D cell lines. Responses to tamoxifen and chemotherapy drugs were determined in MCF-7 and T-47D cells with Noggin over-expression using MTT assay. RESULTS: Noggin expression was negatively correlated with ERα in breast cancers. Noggin was up-regulated upon oestrogen deprivation, an effect that was eliminated by E2 Furthermore, increased levels of phosphorylated Smad1/5/8 were observed in the oestrogen-deprived MCF-7 and T-47D cells, which was prevented by E2 and LDN-193189, respectively. BMP7-induced Noggin expression and activation of Smad1/5/8 was also prevented by E2 and LDN-193189. Noggin over-expression resulted in an increase in the proliferation of both MCF-7 and T-47D cells. MCF-7 and T-47D cells over-expressing Noggin exhibited a good tolerance to tamoxifen (TAM), DTX, and 5-FU, but the percentage of viable cells was higher compared with the controls. CONCLUSION: Noggin expression can be repressed by oestrogen through inference with the BMP/Smad signalling. Over-expression of Noggin promotes the proliferation of MCF-7 and T-47D cells, contributing to drug resistance.

A Spatio-Temporal-Dependent Requirement of Sonic Hedgehog in the Early Development of Sclerotome-Derived Vertebrae and Ribs.

Derived from axial structures, Sonic Hedgehog (Shh) is secreted into the paraxial mesoderm, where it plays crucial roles in sclerotome induction and myotome differentiation. Through conditional loss-of-function in quail embryos, we investigate the timing and impact of Shh activity during early formation of sclerotome-derived vertebrae and ribs, and of lateral mesoderm-derived sternum. To this end, Hedgehog interacting protein (Hhip) was electroporated at various times between days 2 and 5. While the vertebral body and rib primordium showed consistent size reduction, rib expansion into the somatopleura remained unaffected, and the sternal bud developed normally. Additionally, we compared these effects with those of locally inhibiting BMP activity. Transfection of Noggin in the lateral mesoderm hindered sternal bud formation. Unlike Hhip, BMP inhibition via Noggin or Smad6 induced myogenic differentiation of the lateral dermomyotome lip, while impeding the growth of the myotome/rib complex into the somatic mesoderm, thus affirming the role of the lateral dermomyotome epithelium in rib guidance. Overall, these findings underscore the continuous requirement for opposing gradients of Shh and BMP activity in the morphogenesis of proximal and distal flank skeletal structures, respectively. Future research should address the implications of these early interactions to the later morphogenesis and function of the musculo-skeletal system and of possible associated malformations.

Black Phosphorus-Based Dynamic Self-Healing Hydrogel to Integrate Demineralized Bone Matrix and Noggin-Targeting siRNA for Synergistic Osteogenesis.

Although a demineralized bone matrix (DBM) is often used as an alternative to an autologous bone graft, its clinical application is still hampered by easy dispersion of DBM particles and insufficient osteoinductivity in the defect site. Herein, we designed a self-healing hydrogel for DBM that can rapidly restore its structural integrity after damage based on amino-rich black phosphorus (BP) nanosheets and aldehyde-functionalized hyaluronic acid (AHA). Given the increased expression of bone morphogenetic protein (BMP) antagonists by DBM stimulation, the osteogenic potency of DBM in the hydrogel carrier was further enhanced by abrogating the BMP antagonism. The BP/AHA hydrogel provided dynamic polymer-nanosheet networks that combine injectability, modability, and physical stability with high DBM loading, where the BP nanosheets served as osteogenic cross-linkers to promote biomineralization and deliver siRNA to suppress undesirable expression of BMP antagonist noggin by DBM. As a result, the BP/AHA hydrogel integrated with DBM and noggin-targeting siRNA synergistically promoted osteogenic differentiation of mesenchymal stem cells by enhancing BMP/Smad signaling. This work demonstrates a promising strategy to improve the efficacy of bone regeneration using bone graft.

Zhuang-Gu-Fang intervenes vasculogenic and osteogenic coupling in GK rats through Notch1/Noggin/VEGF pathway.

Background: Zhuang-Gu-Fang (ZGF) has been proved to treat osteoporosis in ovariectomized rats by increasing osteogenic related factors Leptin, Ghrelin and Peptide YY(PYY). However, the mechanism of ZGF in the treatment of diabetic osteoporosis (DOP) remains unclear. The aim of this study was to explore the therapeutic effect of ZGF on DOP and its potential molecular mechanism. Methods: Using GK rats as models, the pharmacodynamic effects of ZGF on bone loss were evaluated by hematoxylin-eosin (H&E) staining and micro-computed.tomography (micro-CT). The expression levels of CD31 and endomucin (Emcn) were detected by immunofluorescence to assess the role of ZGF in angiogenic osteogenic coupling. Finally, real-time quantitative PCR (RT-PCR) and Western Blot (WB)were used to detect the expression levels of osteogenic and angiogenesis-related genes and proteins Notch1, Noggin and vascular endothelial growth factor (VEGF). Results: Administration of ZGF demonstrated a significant mitigation of bone loss attributable to elevated glucose levels. H&E staining and micro-CT showed that ZGF notably improved the integrity of the trabecular and cortical bone microarchitecture. Moreover, ZGF was found to augment the density of type H vessels within the bone tissue, alongside elevating the expression levels of Osterix, a transcription factor pivotal for bone formation. Furthermore, our findings suggest that ZGF facilitates the activation of the Notch1/Noggin/VEGF pathway, indicating a potential mechanism through which ZGF exerts its osteoprotective effects. Conclusion: Our results suggest that ZGF potentially facilitates the formation of type H vessels through the Notch1/Noggin/VEGF pathway. This action not only enhances angiogenic-osteogenic coupling but also contributes to the improvement of bone structure and density. Consequently, ZGF emerges as a promising therapeutic agent for the prevention and management of DOP, offering a novel approach by leveraging angiogenesis-dependent osteogenesis.

"And it was the worst possible result, because it actually worked:" An interview with Richard Harland.

One hundred years ago, Hilde Mangold and Hans Spemann published their seminal paper on what came to be known as The Organizer, but seven decades would pass before the molecular basis of this remarkable phenomenon was revealed. Richard Harland and his laboratory played a key role in that discovery, and in this interview he discusses not just the science and the people but also other important factors like mental health and luck.

Toward the Development of a Tissue Engineered Gradient Utilizing CRISPR-Guided Gene Modulation.

Cellular, compositional, and mechanical gradients are found throughout biological tissues, especially in transition zones between tissue types. Yet, strategies to engineer such gradients have proven difficult due to the complex nature of these tissues. Current strategies for tissue engineering complex gradients often utilize stem cells; however, these multipotent cells require direction from environmental cues, which can be difficult to control both in vitro and in vivo. In this study, we utilize clustered regularly-interspaced short palindromic repeats (CRISPR)-guided gene modulation to direct the differentiation of multipotent adipose-derived stem cells (ASCs) to demonstrate the effectiveness of CRISPR-engineered cells in tissue engineering applications. Specifically, we screen CRISPR-interference (CRISPRi) constructs targeting the promotors of selected osteogenic inhibitors and demonstrate that ASC osteogenic differentiation and mineral deposition can be regulated with CRISPRi targeting of Noggin without the use of exogenous growth factors in tissue engineered constructs. As a proof of concept, we combine three technologies developed out of our laboratories to demonstrate the controlled deposition of these engineered cells in a gradient with CRISPR-activation multiplex-engineered aggrecan/collagen type-II-chondrogenic ASCs on a high density anisotropic type I collagen construct to create a cell and tissue gradient similar to the fibrocartilage-to-mineralized-fibrocartilage gradient in the enthesis. Our results display the promise of CRISPR-engineered ASCs to produce tissue gradients, similar to what is observed in native tissue.

The Molecular Mechanism of Body Axis Induction in Lampreys May Differ from That in Amphibians.

Lamprey homologues of the classic embryonic inducer Noggin are similar in expression pattern and functional properties to Noggin homologues of jawed vertebrates. All noggin genes of vertebrates apparently originated from a single ancestral gene as a result of genome duplications. nogginA, nogginB and nogginC of lampreys, like noggin1 and noggin2 of gnathostomes, demonstrate the ability to induce complete secondary axes with forebrain and eye structures when overexpressed in Xenopus laevis embryos. According to current views, this finding indicates the ability of lamprey Noggin proteins to suppress the activity of the BMP, Nodal/Activin and Wnt/beta-catenin signaling pathways, as shown for Noggin proteins of gnathostomes. In this work, by analogy with experiments in Xenopus embryos, we attempted to induce secondary axes in the European river lamprey Lampetra fluviatilis by injecting noggin mRNAs into lamprey eggs in vivo. Surprisingly, unlike what occurs in amphibians, secondary axis induction in the lampreys either by noggin mRNAs or by chordin and cerberus mRNAs, the inductive properties of which have been described, was not observed. Only wnt8a mRNA demonstrated the ability to induce secondary axes in the lampreys. Such results may indicate that the mechanism of axial specification in lampreys, which represent jawless vertebrates, may differ in detail from that in the jawed clade.

Mechanistic insights into the spontaneous induction of bone formation.

The grand discovery of morphogens, or "form-generating substances", revealed that tissue morphogenesis is initiated by soluble molecular signals or morphogens primarily belonging to the transforming growth factor-ß (TGF-ß) supergene family. The regenerative potential of bone rests on its extracellular matrix, which is the repository of several morphogens that tightly control cellular differentiating pathways, cellular matrix deposition and remodeling. Alluringly, the matrix also contains specific factors transferred from the heterotopic implanted bone matrices initiating "Tissue Induction", as provocatively described in Nature in 1945. Later, it was found that selected genes and gene products of the TGF-ß supergene family singly, synchronously, and synergistically mastermind the induction of bone formation. This review describes the phenomenon of the spontaneous and/or intrinsic osteoinductivity of calcium phosphate-based biomaterials and titanium' constructs without the applications of soluble osteogenetic molecular signals. The review shows the spontaneous induction of bone formation initiated by Ca++ activating stem cell differentiation and up-regulation of bone morphogenetic proteins genes. Expressed gene products are embedded into the concavities of the calcium phosphate-based substrata, initiating bone formation as a secondary response. Pure titanium's substrata do not initiate the spontaneous induction of bone formation. The induction of bone is solely dependent on acid, alkali and heat treatments to form apatite layers on the treated titanium surfaces. The induction of bone formation is achieved exclusively by apatite-based biomaterial surfaces. The hydroxyapatite, in its various forms and geometric configurations, finely tunes the induction of bone formation in heterotopic sites. Cellular differentiation by fine-tuning of the cellular molecular machinery is initiated by specific geometric modularity of the hydroxyapatite substrata that push cellular buttons that start the ripple-like cascade of "Tissue Induction", generating newly formed ossicles with bone marrow in heterotopic extraskeletal sites. The highlighted mechanistic insights into the spontaneous induction of bone formation are a research platform invocating selected molecular elements to construct the induction of bone formation.

Downregulated BMP-Smad1/5/8 signaling causes emphysema via dysfunction of alveolar type II epithelial cells.

Bone morphogenetic protein (BMP)-Smad1/5/8 signaling plays a crucial regulatory role in lung development and adult lung homeostasis. However, it remains elusive whether BMP-Smad1/5/8 signaling is involved in the pathogenesis of emphysema. In this study, we downregulated BMP-Smad1/5/8 signaling by overexpressing its antagonist Noggin in adult mouse alveolar type II epithelial cells (AT2s), resulting in an emphysematous phenotype mimicking the typical pathological features of human emphysema, including distal airspace enlargement, pulmonary inflammation, extracellular matrix remodeling, and impaired lung function. Dysregulation of BMP-Smad1/5/8 signaling in AT2s leads to inflammatory destruction dominated by macrophage infiltration, associated with reduced secretion of surfactant proteins and inhibition of AT2 proliferation and differentiation. Reactivation of BMP-Smad1/5/8 signaling by genetics or chemotherapy significantly attenuated the morphology and pathophysiology of emphysema and improved the lung function in Noggin-overexpressing lungs. We also found that BMP-Smad1/5/8 signaling was downregulated in cigarette smoke-induced emphysema, and that enhancing its activity in AT2s prevented or even reversed emphysema in the mouse model. Our data suggest that BMP-Smad1/5/8 signaling, located at the top of the signaling cascade that regulates lung homeostasis, represents a key molecular regulator of alveolar stem cell secretory and regenerative function, and could serve as a potential target for future prevention and treatment of pulmonary emphysema. © 2023 The Pathological Society of Great Britain and Ireland.

DLL4/Notch blockade disrupts mandibular advancement-induced condylar osteogenesis by inhibiting H-type angiogenesis.

BACKGROUND: Blocking Delta-like 4 (DLL4)/Notch has emerged as a promising therapeutic target for the treatment of tumours by deregulating angiogenesis. However, DLL4/Notch serves as a negative regulator of angiogenesis in multiple organs while acting as a positive regulator of H-type angiogenesis in postnatal long bones. Therefore, the effect of DLL4/Notch signalling blockade on mandibular condylar osteogenesis attracted our attention. OBJECTIVE: To explore the effect of blocking DLL4/Notch on mandibular advancement (MA)-induced condylar osteogenesis. METHODS: Six-week-old young male C57BL/6J mice (n = 40) were randomly divided into four groups: control group, MA group, MA + Anti-DLL4 group and MA + IgG group. Of note, IgG served as the isotype control for the anti-DLL4. The femurs, tibias and mandibular condyles were collected after sacrificing mice on Day 31 for morphology, micro-computed tomography, immunofluorescence, histology and immunohistochemistry evaluation. RESULTS: First, DLL4/Notch blockade shortened femoral length and reduced bone mass by inhibiting H-type angiogenesis. Second, DLL4/Notch blockade disrupted MA-induced condylar head volume and quality by inhibiting H-type angiogenesis. Mechanistically, blocking DLL4/Notch reduced the number of runt-related transcription factor 2+ (RUNX2+ ) early osteoprogenitors and the expression of Noggin protein in the condylar subchondral bone by inhibiting H-type angiogenesis. In addition, blockade of DLL4/Notch also destroyed the condylar cartilage layer. CONCLUSION: DLL4/Notch blockade results in shortened femurs and osteopenia, as well as impaired MA-induced condylar osteogenic volume and quality in growing mice by inhibiting H-type angiogenesis. Therefore, when blocking DLL4/Notch is used as a treatment target for diseases, attention should be paid to its impact on the bone mass of mandibular condyle.

Noggin Protein can Induce the Differentiation of Rat Bone Marrow Mesenchymal Stem Cells to Neurons and Repair Spinal Cord Injury.

BACKGROUND: Addressing spinal cord injury (SCI) through stem cell therapy is currently at the forefront of medical research despite its complexity. In this study, we investigated the potential of the Noggin protein in promoting the differentiation of rat bone marrow mesenchymal stem cells (BMSCs) into neuronal cells. We transplanted induced cells into a rat model with spinal cord injury. This exploration proposes an innovative perspective on stem cell therapies for spinal cord injuries. METHODS: Rat BMSCs were isolated utilizing the bone marrow cell apposition method; The multidirectional differentiation of rat BMSCs was identified by lipid induction and osteogenic induction; Rat BMSCs were induced by different concentrations of Noggin protein and different induction times; Nissel staining was used to identify the induced neuronal-like cells; The expression of synaptic protein Ⅰ (SYN1), glial fibrillary acidic protein (GFAP), and neurofilament protein 200 (NF200) in neuron-like cells was detected by immunofluorescence assay. Rats were randomly divided into a control group and a neuron-like cell group; A rat spinal cord injury model was produced, and neuron-like cells obtained from induction were transplanted into the rat's SCI. The recovery of the rats' hind limbs' motor function was detected by the Basso, Beattie, and Bresnahan (BBB) scores, and the changes in the expression of NF200 mRNA at the spinal cord injury were detected by quantitative real time polymerase chain reaction (qRT-PCR). RESULTS: Our cultured rat BMSCs had a long spindle-shaped morphology and stained positively for oil red O after lipogenic induction and modified alizarin red S after osteogenic induction. Nissel staining of cells obtained from rat BMSCs induced by Noggin protein was positive. Immunofluorescence results showed that the induced neuronal-like cells positively expressed NF200 and SYN1, and negatively expressed GFAP. After local transplantation of induced neuronal-like cells in the rat SCI model, the BBB scores in the neuron-like cell group were higher than those in the control group at 1 w, 2 w, and 4 w, with statistically different results (p < 0.05). According to qRT-PCR results, NF200 at the spinal cord injury in the neuron-like cell group was higher than that in the control group at 12 h, 3 d, 1 w, 2 w, and 4 w, with statistically significant differences in results (p < 0.05). CONCLUSIONS: Our findings indicate that Noggin protein effectively facilitates the differentiation of rat BMSCs into neuronal cells, highlighting its potential as a therapeutic agent for repairing spinal cord injuries. This study elucidates a promising avenue in stem cell research, contributing a novel approach to regenerative strategies for spinal cord injuries.

Essential Role of BMP4 Signaling in the Avian Ceca in Colorectal Enteric Nervous System Development.

The enteric nervous system (ENS) is principally derived from vagal neural crest cells that migrate caudally along the entire length of the gastrointestinal tract, giving rise to neurons and glial cells in two ganglionated plexuses. Incomplete migration of enteric neural crest-derived cells (ENCDC) leads to Hirschsprung disease, a congenital disorder characterized by the absence of enteric ganglia along variable lengths of the colorectum. Our previous work strongly supported the essential role of the avian ceca, present at the junction of the midgut and hindgut, in hindgut ENS development, since ablation of the cecal buds led to incomplete ENCDC colonization of the hindgut. In situ hybridization shows bone morphogenetic protein-4 (BMP4) is highly expressed in the cecal mesenchyme, leading us to hypothesize that cecal BMP4 is required for hindgut ENS development. To test this, we modulated BMP4 activity using embryonic intestinal organ culture techniques and retroviral infection. We show that overexpression or inhibition of BMP4 in the ceca disrupts hindgut ENS development, with GDNF playing an important regulatory role. Our results suggest that these two important signaling pathways are required for normal ENCDC migration and enteric ganglion formation in the developing hindgut ENS.

Noggin contributes to brain metastatic colonization of lung cancer cells.

BACKGROUND: Brain metastasis is a common complication among patients with lung cancer, yet the underlying mechanisms remain unclear. In this study, we aimed to investigate the pathogenesis of brain metastasis in lung cancer. METHODS: We established highly colonizing metastatic lung cancer cells, A549-M2, through multiple implantations of A549 human lung cancer cells in the carotid artery of athymic nude mice. RESULTS: Compared to parental cells (M0), M2 cells demonstrated slower growth in culture plates and soft agar, as well as lower motility and higher adhesion, key characteristics of mesenchymal-epithelial transition (MET). Further analysis revealed that M2 cells exhibited decreased expression of epithelial-mesenchymal transition markers, including ZEB1 and Vimentin. M2 cells also demonstrated reduced invasiveness in co-culture systems. RNA sequencing and gene set enrichment analysis confirmed that M2 cells underwent MET. Intriguingly, depletion of Noggin, a BMP antagonist, was observed in M2 cells, and replenishment of Noggin restored suppressed migration and invasion of M2 cells. In addition, Noggin knockdown in control M0 cells promoted cell attachment and suppressed cell migration, suggesting that Noggin reduction during brain colonization causes inhibition of migration and invasion of metastatic lung cancer cells. CONCLUSIONS: Our results suggest that lung cancer cells undergo MET and lose their motility and invasiveness during brain metastatic colonization, which is dependent on Noggin.

Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage.

Non-adherent culture is critical for the transdifferentiation of stem cells from mesoderm to neuroectoderm. Sphere culture has been reported to directly induce the adipose tissue cells to neural stem cells. Here we aimed to evaluate continuous non-adherent culture on the transdifferentiation potential of human adipose-derived stem cells (ASCs) into retinal lineage. Human ASCs were induced into retinal lineage by the treatment of noggin, dickkopf-related protein 1, and IGF-1 (NDI) under adherent and non-adherent culture. The NDI induction treatment with the adherent culture for 21 days promoted robust expression of retinal markers in the induced ASCs as compared to those without NDI induction on the adherent culture. With continuous non-adherent culture for 21 days, human ASCs could highly express retinal marker genes even without NDI induction treatment as compared to those on the adherent culture. The combination of continuous non-adherent culture with the NDI induction did not show a significant upregulation of the retinal marker expression as compared to either NDI induction with the adherent culture or continuous non-adherent culture without NDI induction treatment. In summary, both non-adherent culture and NDI induction medium could independently promote the transdifferentiation of human ASCs into retinal lineage. Yet, their combination did not produce an enhancement effect.

Enhanced Osteogenic Potential of Noggin Knockout C2C12 Cells on BMP-2 Releasing Silk Scaffolds.

The CRISPR/Cas9 mechanism offers promising therapeutic approaches for bone regeneration by stimulating or suppressing critical signaling pathways. In this study, we aimed to increase the activity of BMP-2 signaling through knockout of Noggin, thereby establishing a synergistic effect on the osteogenic activity of cells in the presence of BMP-2. Since Noggin is an antagonist expressed in skeletal tissues and binds to subunits of bone morphogenetic proteins (BMPs) to inhibit osteogenic differentiation, here Noggin expression was knocked out using the CRISPR/Cas9 system. In accordance with this purpose, C2C12 (mouse myoblast) cells were transfected with CRISPR/Cas9 plasmids. Transfection was achieved with Lipofectamine and confirmed with intense fluorescent signals in microscopic images and deletion in target sequence in Sanger sequencing analysis. Thus, Noggin knockout cells were identified as a new cell source for tissue engineering studies. Then, the transfected cells were seeded on highly porous silk scaffolds bearing BMP-2-loaded silk nanoparticles (30 ng BMP-2/mg silk nanoparticle) in the size of 288 ± 62 nm. BMP-2 is released from the scaffolds in a controlled manner for up to 60 days. The knockout of Noggin by CRISPR/Cas9 was found to synergistically promote osteogenic differentiation in the presence of BMP-2 through increased Coll1A1 and Ocn expression and mineralization. Gene editing of Noggin and BMP-2 increased almost 2-fold Col1A1 expression and almost 3-fold Ocn expression compared to the control group. Moreover, transfected cells produced extracellular matrix (ECM) containing collagen fibers on the scaffolds and mineral-like structures were formed on the fibers. In addition, mineralization characterized by intense Alizarin red staining was detected in transfected cells cultured in the presence of BMP-2, while the other groups did not exhibit any mineralized areas. As has been demonstrated in this study, the CRISPR/Cas9 mechanism has great potential for obtaining new cell sources to be used in tissue engineering studies.

Expression and regulation of Noggin4 gene in chicken ovarian follicles and its role in the proliferation and differentiation of granulosa cells.

As a member of Noggin family, Noggin4 is reported to play an important role in the formation of head structure during the embryo development of Xenopus laevis and chicken. We previously detected an increase of Noggin4 transcript in the granulosa cells of chicken hierarchal follicles (Post-GCs) compared to pre-hierarchal follicles (Pre-GCs) by ONT transcriptome sequencing. To further clarify the role of Noggin4 in chicken follicle selection, in this study, we investigated its expression, regulation and function in follicles and granulosa cells. The mRNA expression of chicken Noggin4 exhibited dynamic changes during follicle development. It was significantly higher in the small yellow follicles than in the small white, F6, F5 and F4 follicles, and also increased in Post-GCs than in Pre-GCs. The Noggin4 mRNA could be stimulated by follicle stimulating hormone (FSH) and bone morphogenetic protein 4 (BMP4) in both Pre-GCs and Post-GCs. However, the estrogen and progesterone could exert opposing transcriptional regulations on Noggin 4 mRNA in both Pre- and Post-GCs. In chicken Post-GCs, knockdown of Noggin4 by siRNA reduced the mRNA expression of steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), but increased that of Wnt family member 4 (Wnt4), while overexpression of Noggin4 significantly decreased the mRNA expression of Wnt4 but had no marked effects on that of STAR and CYP11A1. Moreover, Noggin4 significantly decreased the mRNA expression of BMP4 in both Pre-GCs and Post-GCs. Overexpression of Noggin4 inhibited the proliferation of both Pre-GCs and Post-GCs. These data collectively suggest an important role of Noggin4 in chicken follicle selection, especially on the proliferation of granulosa cells.

Complementary modulation of BMP signaling improves bone healing efficiency.

The bone morphogenetic protein (BMP) signaling pathway plays a crucial role in bone development and regeneration. While BMP-2 is widely used as an alternative to autograft, its clinical application has raised concerns about adverse side effects and deteriorated bone quality. Therefore, there is a need to develop more sophisticated approaches to regulate BMP signaling and promote bone regeneration. Here, we present a novel complementary strategy that targets both BMP antagonist noggin and agonist Trb3 to enhance bone defect repair without the application of exogenous BMP-2. In vitro studies showed that overexpression of Trb3 with simultaneous noggin suppression significantly promotes osteogenic differentiation of mesenchymal stem cells. This was accompanied by increased BMP/Smad signaling. We also developed sterosome nanocarriers, a non-phospholipid liposomal system, to achieve non-viral mediated noggin suppression and Trb3 overexpression. The gene-loaded sterosomes were integrated onto an apatite-coated polymer scaffold for in vivo calvarial defect implantation, resulting in robust bone healing compared to BMP-2 treatments. Our work provides a promising alternative for high-quality bone formation by regulating expression of BMP agonists and antagonists.

Myo/Nog Cells: The Jekylls and Hydes of the Lens.

Herein, we review a unique and versatile lineage composed of Myo/Nog cells that may be beneficial or detrimental depending on their environment and nature of the pathological stimuli they are exposed to. While we will focus on the lens, related Myo/Nog cell behaviors and functions in other tissues are integrated into the narrative of our research that spans over three decades, examines multiple species and progresses from early stages of embryonic development to aging adults. Myo/Nog cells were discovered in the embryonic epiblast by their co-expression of the skeletal muscle-specific transcription factor MyoD, the bone morphogenetic protein inhibitor Noggin and brain-specific angiogenesis inhibitor 1. They were tracked from the epiblast into the developing lens, revealing heterogeneity of cell types within this structure. Depletion of Myo/Nog cells in the epiblast results in eye malformations arising from the absence of Noggin. In the adult lens, Myo/Nog cells are the source of myofibroblasts whose contractions produce wrinkles in the capsule. Eliminating this population within the rabbit lens during cataract surgery reduces posterior capsule opacification to below clinically significant levels. Parallels are drawn between the therapeutic potential of targeting Myo/Nog cells to prevent fibrotic disease in the lens and other ocular tissues.

Decrease levels of bone morphogenetic protein 6 and noggin in chronic schizophrenia elderly.

Objective: Bone morphogenetic protein 6 (BMP6) and noggin both have been implicated in the pathophysiology of chronic dementia, and chronic schizophrenia (SCZ) has high risk for progressing to dementia in later life. The current study investigated the relationship between blood BMP6/noggin levels and cognitive function in chronic SCZ elderly. Methods: A total of 159 chronic SCZ elderly and 171 community normal controls (NC) were involved in the present study. Blood cytokines including BMP6 and its antagonist-noggin, and cognitive function were measured in all subjects, 157 subjects among them received apolipoprotein E (APOE) genotype test, and 208 subjects received cognitive assessment at 1-year follow-up. Results: Chronic SCZ elderly had decreased levels of blood BMP6 and noggin compared to healthy controls, especially in the subgroup of chronic SCZ with dementia. Blood BMP6 combing with noggin could distinguish chronic SCZ from NC elderly. APOE ε4 carriers had lower levels of BMP6 than APOE non-ε4 carriers under chronic SCZ. Conclusions: There was a significant relationship of blood BMP6/noggin with cognitive performance in chronic SCZ.

Osteochondrogenesis by TGF-ß3, BMP-2 and noggin growth factor combinations in an ex vivo muscle tissue model: Temporal function changes affecting tissue morphogenesis.

In the absence of clear molecular insight, the biological mechanism behind the use of growth factors applied in osteochondral regeneration is still unresolved. The present study aimed to resolve whether multiple growth factors applied to muscle tissue in vitro, such as TGF-ß3, BMP-2 and Noggin, can lead to appropriate tissue morphogenesis with a specific osteochondrogenic nature, thereby revealing the underlying molecular interaction mechanisms during the differentiation process. Interestingly, although the results showed the typical modulatory effect of BMP-2 and TGF-ß3 on the osteochondral process, and Noggin seemingly downregulated specific signals such as BMP-2 activity, we also discovered a synergistic effect between TGF-ß3 and Noggin that positively influenced tissue morphogenesis. Noggin was observed to upregulate BMP-2 and OCN at specific time windows of culture in the presence of TGF-ß3, suggesting a temporal time switch causing functional changes in the signaling protein. This implies that signals change their functions throughout the process of new tissue formation, which may depend on the presence or absence of specific singular or multiple signaling cues. If this is the case, the signaling cascade is far more intricate and complex than originally believed, warranting intensive future investigations so that regenerative therapies of a critical clinical nature can function properly.