Bone Morphogenetic Protein Research Articles

Hierarchically structured nanofibrous scaffolds spatiotemporally mediate the osteoimmune micro-environment and promote osteogenesis for periodontitis-related alveolar bone regeneration

Periodontitis suffer from inflammation-induced destruction of periodontal tissues, resulting in the serious loss of alveolar bone. Controlling inflammation and promoting bone regeneration are two crucial aspects for periodontitis-related alveolar bone defect treatment. Herein, we developed a hierarchically structured nanofibrous scaffold with a nano-embossed sheath and a bone morphogenetic protein 2-loaded core to match the periodontitis-specific features that spatiotemporally modulated the osteoimmune environment and promoted periodontal bone regeneration. We investigated the potential of this unique scaffold to treat periodontitis-related alveolar bone defects in vivo and in vitro. The results demonstrated that the hierarchically structured scaffold effectively reduced the inflammatory levels in macrophages and enhanced the osteogenic potential of bone mesenchymal stem cells in an inflammatory microenvironment. Moreover, in vivo experiments revealed that the hierarchically structured scaffold significantly ameliorated inflammation in the periodontium and inhibited alveolar bone resorption. Notably, the hierarchically structured scaffold also exhibited a prolonged effect on promoting alveolar bone regeneration. These findings highlight the significant therapeutic potential of hierarchically structured nanofibrous scaffolds for the treatment of periodontitis, and their promising role in the field of periodontal tissue regeneration. Statement of Significance: We present a novel hierarchically structured nanofibrous scaffold of coupling topological and biomolecular signals for precise spatiotemporal modulation of the osteoimmune micro-environment. Specifically, the scaffold was engineered via coaxial electrospinning of the poly(ε-caprolactone) sheath and a BMP-2/polyvinyl alcohol core, followed by surface-directed epitaxial crystallization to generate cyclic nano-lamellar embossment on the sheath. With this unique hierarchical structure, the cyclic nano-lamellar sheath provided a direct nano-topographical cue to alleviate the osteoimmune environment, and the stepwise release of BMP-2 from the core provided a biological cue for bone regeneration. This research underscores the potential of hierarchically structured nanofibrous scaffolds as a promising therapeutic approach for periodontal tissue regeneration and highlights their role in advancing periodontal tissue engineering.

Melatonin Protects Against Mitochondrial Dyshomeostasis and Ovarian Damage Caused by Chronic Unpredictable Mild Stress Through the eIF2α-AFT4 Signaling Pathway in Mice.

Stress is an emotional state caused by an unexpected external environmental change or stimulus, and several experiments have demonstrated its negative impact on ovarian function, ultimately affecting reproductive ability. Melatonin (MT) has been shown to facilitate oocyte maturation and enhance ovarian function by regulating mitochondrial function. However, the specific effect and underlying molecular mechanisms of MT on stress-induced ovarian dysfunction remain largely unknown. In this study, we established a mouse model of chronic unpredictable mild stress (CUMS) to investigate its impact on ovarian function. Our findings revealed that CUMS led to premature ovarian insufficiency (POI) in mice, characterized by a reduction in follicle numbers and decreased levels of anti-Müllerian hormone (AMH) and bone morphogenetic protein 15 (BMP15). Furthermore, CUMS caused decreased expression of mitochondrial fission protein 1 (FIS1) and enhanced level of mitochondrial fusion protein optic atrophy 1(OPA1), mitofusin1(MFN1), as well as nucleus-encoded protein succinate dehydrogenase complex A (SDHA), reflecting mitochondrial dyshomeostasis. Additionally, CUMS resulted in excessive autophagy and apoptosis. However, MT reversed these effects and improved ovarian damage. Importantly, the protective effects of MT were mediated through the inhibition of the eIF2α-AFT4 pathway. Overall, this study provides valuable insights into the treatment of POI caused by CUMS.

BMP3b regulates bone mass by inhibiting BMP signaling

Bone morphogenetic protein 3b (BMP3b), also known as growth differentiation factor 10 (GDF10), is a non-osteogenic BMP highly expressed in the skeleton. Although in vitro studies have shown that BMP3b suppresses osteoblast differentiation, the physiological role of BMP3b in regulating bone mass in vivo remains unknown. Here, we show that BMP3b deletion in mice leads to a high bone mass phenotype via an unexpected novel mechanism involving de-repression of canonical BMP/Smad signaling. BMP3b null mice were viable, and exhibited no significant difference in body size compared to wildtype control. Trabecular bone parameters assessed by histomorphometry and μCT, revealed a significant increase in bone volume and bone mineral density. Expression of osteoblast-differentiation genes were elevated in bone tissue of BMP3b null mice, whereas expression of osteoclast-related genes remained unchanged. Consistent with this, Bmp3b was highly expressed in osteoblasts relative to osteoclast cells. Ex-vivo culture of primary bone marrow mesenchymal stem cells (BMSCs) and primary bone marrow-derived osteoclasts revealed that inactivation of BMP3b enhances osteogenesis without affecting osteoclastogenesis. Mechanistically, we found that BMP3b suppressed BMP4-induced Smad1/5 phosphorylation and inhibited the activity of a BMP4-driven Id-1 luciferase reporter. Protein-protein interaction assays revealed that BMP3b competitively interfered with the association of BMP4 and BMP type I receptors. These findings suggest that BMP3b regulates bone mass by acting as a BMP receptor antagonist. Thus, maintenance of bone mass involves antagonism of canonical BMP/Smad signaling by a member of the BMP family.

Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding.

Acromesomelic chondrodysplasias are a rare subgroup of the clinically and genetically heterogeneous osteochondrodysplasias that are characterised by abnormalities in the limb development and short stature. Here, we report a 2-year-old boy, offspring of consanguineous parents, with acromesomelic dysplasia and postaxial polydactyly in which exome sequencing identified a novel homozygous missense variant in BMPR1B. The patient showed skeletal malformation of both hands and feet that included complex brachydactyly with the thumbs most severely affected, postaxial polydactyly of both hands, shortened toes as well as a bilateral hypoplasia of the fibula. Whole trio exome sequencing was conducted to identify potential genetic variants in the patient. The analysis identified the biallelic variant NM_001203.3:c.821A > G;p.(Gln274Arg) in BMPR1B, a gene encoding bone morphogenetic protein receptor 1B. The skeletal phenotype can be brought in line with the phenotypes of previously reported cases of BMPR1B-associated chondrodysplasias. However, the postaxial polydactyly described here is a novel clinical finding in a BMPR1B-related case; notably, it has previously been reported in other acromesomelic dysplasia cases caused by homozygous pathogenic variants in GDF5-a gene which encodes for growth differentiation factor 5, a high-affinity ligand to BMPR1B.

Healing of Humerus Non-union Fracture Using Recombinant Human Bone Morphogenetic Protein With Bone Graft Compared to Bone Graft Alone: A Systematic Review and Meta-Analysis.

Non-union fractures of the humerus present significant challenges in orthopedic surgery, often requiring advanced treatments to achieve successful bone healing. The study aimed to compare the use of recombinant human bone morphogenetic protein (rhBMP) with bone grafts versus bone grafts alone for treating humerus non-union fractures with regard to healing rate and complications. Six databases, PubMed, ScienceDirect, The Cochrane Library, Scopus, Web of Science, and Google Scholar, were searched for relevant literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and studies were selected according to the set eligibility criteria. Quality assessment was performed using the Mixed Methods Appraisal Tool for randomized controlled trials (RCTs) and non-RCTs. Review Manager (RevMan) version 5.4 (2020, The Cochrane Collaboration, London, United Kingdom) was utilized for meta-analysis at a significance level of 0.01. Eighteen research papers were included for qualitative and quantitative analysis. Due to the unavailability of RCTs, data from the two studies were combined. The pooled data from 16 studies for effectiveness regarding union achieved forrhBMP with bone graft versus bone graft alone was 0.65 (95%CI: 0.07-6.38, I2 =67%, p=0.02). For rhBMP-2 and rhBMP-7 with bone graft, the pooled data was 0.09 (95%CI: 0.00-3.63) with high heterogeneity (I2 =88%) and statistically significant differences (p<0.00001). In the sub-group analysis, the pooled data for infection rate was 1.18 (95%CI, 0.37-3.73) with 39% heterogeneity and a non-significant difference (p=0.10). AddingrhBMP to bone grafts may not significantly improve union rates compared to bone graft alone in humerus non-union fractures. However, the trend shows increased infection rates with rhBMP usage. Further high-quality RCTs are warranted to confirm these findings and elucidate the optimal management strategy for humerus non-union fractures.

BMP Antagonist Gremlin 2 Regulates Hippocampal Neurogenesis and Is Associated with Seizure Susceptibility and Anxiety.

The Bone Morphogenetic Protein (BMP) signaling pathway is vital in neural progenitor cell proliferation, specification, and differentiation. The BMP signaling antagonist Gremlin 2 (Grem2) is the most potent natural inhibitor of BMP expressed in the adult brain; however its function remains unknown. To address this knowledge gap, we have analyzed mice lacking Grem2 via homologous recombination (Grem2-/- ). Histological analysis of brain sections revealed significant scattering of CA3 pyramidal cells within the dentate hilus in the hippocampus of Grem2-/- mice. Furthermore, the number of proliferating neural stem cells and neuroblasts was significantly decreased in the subgranular zone of Grem2-/- mice compared with that of wild-type (WT) controls. Due to the role of hippocampal neurogenesis in neurological disorders, we tested mice on a battery of neurobehavioral tests. Grem2-/- mice exhibited increased anxiety on the elevated zero maze in response to acute and chronic stress. Specifically, male Grem2-/- mice showed increased anxiogenesis following chronic stress, and this was correlated with higher levels of BMP signaling and decreased proliferation in the dentate gyrus. Additionally, when chemically challenged with kainic acid, Grem2-/- mice displayed a higher susceptibility to and increased severity of seizures compared with WTs. Together, our data indicate that Grem2 regulates BMP signaling and is vital in maintaining homeostasis in adult hippocampal neurogenesis and structure. Furthermore, the lack of Grem2 contributes to the development and progression of neurogenesis-related disorders such as anxiety and epilepsy.

Smart Implantable Hydrogel for Large Segmental Bone Regeneration.

Large segmental bone defects often lead to nonunion and dysfunction, posing a significant challenge for clinicians. Inspired by the intrinsic bone defect repair logic of "vascularization and then osteogenesis", this study originally reports a smart implantable hydrogel (PDS-DC) with high mechanical properties, controllable scaffold degradation, and timing drug release that can proactively match different bone healing cycles to efficiently promote bone regeneration. The main scaffold of PDS-DC consists of polyacrylamide, polydopamine, and silk fibroin, which endows it with superior interfacial adhesion, structural toughness, and mechanical stiffness. In particular, the adjustment of scaffold cross-linking agent mixing ratio can effectively regulate the in vivo degradation rate of PDS-DC and intelligently satisfy the requirements of different bone defect healing cycles. Ultimately, PDS hydrogel loaded with free desferrioxamine (DFO) and CaCO3 mineralized ZIF-90 loaded bone morphogenetic protein-2 (BMP-2) to stimulate efficient angiogenesis and osteogenesis. Notably, DFO is released rapidly by free diffusion, whereas BMP-2 is released slowly by pH-dependent layer-by-layer disintegration, resulting in a significant difference in release time, thus matching the intrinsic logic of bone defect repair. In vivo and in vitro results confirm that PDS-DC can effectively realize high-quality bone generation and intelligently regulate to adapt to different demands of bone defects.

3D-Printed-Cryogel-Impregnated Functionalized Scaffold Augments Bone Regeneration in Critical Tibia Fracture in Goat.

Critical-size bone trauma injuries present a significant clinical challenge because of the limited availability of autografts. In this study, a photocurable composite comprising of polycaprolactone, polypropylene fumarate, and nano-hydroxyapatite (nHAP) (P─P─H) is printed, which shows good osteoconduction in a rat model. A cryogel composed of gelatin-nHAP (GH) is developed to incorporate osteogenic components, specifically bone morphogenetic protein-2 (BMP-2) and zoledronic acid (ZA), termed as GH+B+Z, which is investigated for osteoinductive property in a rat model. Further, a 3D-printed P─P─H scaffold impregnated with GH+B+Z is designed and implanted in a critical-size defect (25×10×5mm) in goat tibia. After 4 months, the scaffold is well-integrated with adjacent native bone, with osteoinduction observed in the cryogel-filled region and osteoconduction over the printed scaffold. X-ray radiography and micro-CT analysis showed bone in-growth in the treatment group with 45 ± 1.4% bone volume/tissue volume (BV/TV), while the defect remained unhealed in the control group with BV/TV of 10.5 ± 0.5%. Histology showed significant cell infiltration and matrix deposition over the printed P─P─H scaffold and within the GH cryogel site in the treatment group. Immunohistochemical staining depicted significantly higher normalized collagen I intensity in the treatment group (34.45 ± 2.61%) compared to the control group (4.22 ± 0.78).

Gremlin1: a BMP antagonist with therapeutic potential in Oncology.

Gremlins, originating from early 20th-century Western folklore, are mythical creatures known for causing mechanical malfunctions and electronic failures, aptly dubbed "little devils". Analogously, GREM1 acts like a horde of these mischievous entities by antagonizing the bone morphogenetic protein (BMP signaling) pathway or through other non-BMP dependent mechanisms (such as binding to Fibroblast Growth Factor Receptor 1and Epidermal Growth Factor Receptor) contributing to the malignant progression of various cancers. The overexpression of GREM1 promotes tumor cell growth and survival, enhances angiogenesis within the tumor microenvironment, and creates favorable conditions for tumor development and dissemination. Consequently, inhibiting the activity of GREM1 or blocking its interaction with BMP presents a promising strategy for suppressing tumor growth and metastasis. However, the role of GREM1 in cancer remains a subject of debate, with evidence suggesting both oncogenic and tumor-suppressive functions. Currently, several pharmaceutical companies are researching the GREM1 target, with some advancing to Phase I/II clinical trials. This article will provide a detailed overview of the GREM1 target and explore its potential role in cancer therapy.

Biportal Endoscopic Transforaminal Lumbar Interbody Fusion: How to Improve Fusion Rate?

Biportal endoscopic transforaminal lumbar interbody fusion (BE-TLIF) is a minimally invasive surgical technique for treating degenerative lumbar spine conditions. It offers advantages such as reduced soft tissue trauma and lower infection rates, but certain technical aspects may be challenging. The current study aims to identify strategies to enhance the fusion rate in BE-TLIF by addressing these specific challenges. A literature review was conducted on techniques to improve fusion rates in BE-TLIF. The review suggests that lateral-based portals supplemented with medial portals allowed for safe insertion of interbody cages with large footprint. Direct visualization of the disc space with a 30° endoscope assisted with better disc space preparation. Facetectomies performed with osteotomes, rather than burrs, ensured maximum retrieval of autologous bone graft. Utilizing bone morphogenetic proteins with sustained release carriers such as hydroxyapatite can be useful to increase fusion rates of BE-TLIF. To our knowledge, the current literature is the first comprehensive review of strategies to enhance fusion rates in BE-TLIF. The proposed techniques and biological adjuncts are effective means to address key challenges associated with the procedure, and such strategies would potentially shorten the learning curve and improve clinical outcomes. Further clinical studies are required to validate these findings and establish standardized protocols. These findings provide practical solutions to overcome common challenges in BE-TLIF. The suggested techniques would reduce the incidence of pseudarthrosis, improve patient outcomes, and ultimately offer a safer and more reliable option for lumbar interbody fusion patients.

The effects of fulvic acids and low-level laser therapy on orthodontic retention in rats

BackgroundShortening retention time and minimizing relapse rates are ongoing challenges in orthodontics. This study investigated the effects of natural fulvic acids (FAs) and low-level laser therapy (LLLT) on orthodontic retention in rats.MethodsSeventy-two male Sprague-Dawley rats underwent mesial movement of the left maxillary first molar using a 50 g force via a nickel-titanium tension spring. After three weeks of movement, the rats entered the retention phase with retainer wires and were divided into four groups: Control (no intervention), FAs (80 mg/kg orally daily), LLLT (808 nm laser twice weekly), and FAs + LLLT (both treatments). Retainers were removed on days 7, 14, and 21 for a 3-day relapse assessment. Maxillary impressions were analyzed for relapse rates using 3Shape software, alongside histological and immunohistochemical evaluations of bone morphogenetic protein-2 (BMP-2) expression in periodontal tissues, with differences among groups analyzed using an ordinary two-way analysis of variance (ANOVA).ResultsThe relapse rate decreased over time, particularly at 10, 17, and 24 days (p < 0.001). The FAs group did not significantly affect relapse rates compared to the control group (p = 0.084). In contrast, both the LLLT and FAs + LLLT groups significantly reduced relapse rate (p < 0.001), with no significant difference between these groups (p = 0.555). Histological examination revealed active osteoclasts on day 10, decreasing by days 17 and 24. The LLLT and FAs + LLLT groups showed less local cementum resorption and better periodontal fiber arrangement. All treatment groups significantly increased BMP-2 expression (P < 0.05) compared to controls. with LLLT and FAs + LLLT differing significantly from FAs (P < 0.001), though no difference was observed between LLLT and FAs + LLLT (P = 0.578).ConclusionsFAs did not significantly reduce relapse rate with retainers, while LLLT effectively reduced relapse rates, showing no additional benefit from combining FAs with LLLT. Both FAs and LLLT increased BMP-2 expression in PDL fibroblasts but with no synergistic effect.

Sequential release of vancomycin and BMP-2 from chitosan/nano-hydroxyapatite thermosensitive hydrogel for the treatment of chronic osteomyelitis

In this study, we developed scaffolds materials with microspheres to form a double sustained release system.Chitosan/nano-hydroxyapatite (CS-HA) was used as a drug carrier to construct a sustained-release system for Bone morphogenetic protein-2(BMP-2) and Vancomycin (VAN). Furthermore, VAN and BMP-2 loaded microspheres (Ms) were prepared by the emulsion ultrasonic method.The resultant composites were characterized by Scanning electron microscope (SEM), compressive strength, porosity, and biodegradation. The characterization results showed uniform porous and rough surface, enhanced thermal stability, and highest compressive strength ((1.912 ± 0.012) Kpa, the surface of the two microspheres was slightly folded and showed a regular spherical shape.The loading rate of BMP-2 was (59.611 × 10-4 ± 0.023 × 10-4)% and the encapsulation rate was (6.022 ± 0.005)%. The release rate of vancomycin and BMP-2 was 57.194% and 12.968% respectively. Osteogenic differentiation of Bone marrow mesenchymal stem cells (BMSCs) was confirmed by alkaline phosphatase quantification. The deposition of late osteogenic markers (calcium phosphates) detected by Alizarin red, which indicated extracellular matrix mineralization. The results showed that BMP-2/VAN in CS-HA hydrogel successfully achieved the sequential release of the double drugs, which could benefit bone regeneration.

Comprehensive Characterization of Tissue Mineralization in an Ex Vivo Model.

The extensive characterization of tissue mineralization in the context of bone regeneration represents a significant challenge, given the numerous modalities that are currently available for analysis. Here, we propose a workflow for a comprehensive evaluation of new bone formation using a relevant large animal osseous ex vivo explant. A bone defect (diameter = 3.75 mm; depth = 5.0 mm) is created in an explanted sheep femoral head and injected with a macroporous bone substitute loaded with a pro-osteogenic growth factor (bone morphogenetic protein 2 - BMP2). Subsequently, the explant is maintained in culture for a 28-day period, allowing cellular colonization and subsequent bone formation. To evaluate the quality and structure of newly mineralized tissue, the following successive methods are set up: (i) Characterization and high-resolution 3D images of the entire explant using micro-CT, followed by deep learning image analyses to enhance the discrimination of mineralized tissues; (ii) Nano-indentation to determine the mechanical properties of the newly formed tissue; (iii) Histological examinations, such as Hematoxylin/Eosin/Saffron (HES), Goldner's trichrome, and Movat's pentachrome to provide a qualitative assessment of mineralized tissue, particularly with regard to the visualization of the osteoid barrier and the presence of bone cells; (iv) Back-scattering scanning electron microscopy (SEM) mapping with internal reference to quantify the degree of mineralization and provide detailed insights into surface morphology, mineral composition, and bone-biomaterial interface; (v) Raman spectroscopy to characterize the molecular composition of the mineralized matrix and to provide insights into the persistence of BMP2 within the cement through the detection of peptide bonds. This multimodal analysis will provide an effective assessment of newly formed bone and comprehensive qualitative and quantitative insights into mineralized tissues. Through the standardization of these protocols, we aim to facilitate interstudy comparisons and improve the validity and reliability of research findings.

DDIT3 switches osteogenic potential of BMP9 to lipogenic by attenuating Wnt/β-catenin signaling via up-regulating DKK1 in mesenchymal stem cells.

Bone morphogenetic protein 9 (BMP9) functions as a potent inducer of osteogenic differentiation in mesenchymal stem cells (MSCs), holding promise for bone tissue engineering. However, BMP9 also concurrently triggers lipogenic differentiation in MSCs, potentially compromising its osteogenic potential. In this study, we explored the role of DNA damage inducible transcript 3 (DDIT3) in regulating the balance between BMP9-induced osteogenic and lipogenic differentiation in MSCs. Utilizing techniques such as PCR, Western blot, histochemical staining, and in vivo experiments, we analyzed the osteogenic and lipogenic markers induced by BMP9 and delved into the underlying molecular mechanism. We found a significant upregulation of DDIT3 in C3H10T1/2 cells treated with BMP9. This upregulation led to a reduction in BMP9-induced osteogenic markers but an enhancement in lipogenic markers. Conversely, knocking down DDIT3 produced the opposite effects. Furthermore, BMP9-induced bone formation was decreased in the presence of DDIT3, but adipocyte formation was increased. Further investigations demonstrated that BMP9 increased the phosphorylation level of GSK-3β and promoted nuclear translocation of β-catenin, both of which were suppressed by DDIT3. Moreover, DDIT3 decreased the total β-catenin protein level while BMP9 increased the DKK1 protein level, which was further enhanced by DDIT3. Notably, knocking down DKK1 partially reversed the effect of DDIT3 on reducing BMP9-induced osteogenic markers and increasing lipogenic markers. Our findings indicated that DDIT3 enhances lipogenic differentiation by diminishing BMP9's osteogenic potential, possibly through inhibiting Wnt/β-catenin signaling via DKK1 upregulation in MSCs.

Knockdown of BMP7 induced oligodendrocyte apoptosis, demyelination and motor function loss

BackgroundDemyelinating diseases, including multiple sclerosis (MS) and spinal cord injury (SCI), lead to significant neurological deficits primarily due to the loss of oligodendrocytes (OLs). Bone Morphogenetic Protein 7 (BMP7) is expressed abundantly in the central nervous system and previous studies showed its protective effect in reducing OL loss. In this study, we aim to explore BMP7's potential as a biomarker and therapeutic target for demyelinating diseases by investigating its expression and effects on OLs and myelin sheath integrity. MethodWe analyzed multiple Gene Expression Omnibus datasets for BMP7 expression profiles in demyelinating conditions such as MS and SCI. Experimentally, we employed a BMP7 knockdown model in rat spinal cords using adeno-associated virus8 vectors to specifically reduce BMP7 expression. Western blotting, immunofluorescence, and Nissl staining were used to assess the effect on OL and other types of cells. The structure of myelin sheath and locomotor function were evaluated using transmission electron microscopy and BBB scores, and statistical analysis included ROC curves and ANOVA to evaluate BMP7's diagnostic and therapeutic potential. ResultsBMP7 expression consistently decreased across various demyelinating models, and BMP7 knockdown led to increased OL apoptosis through the Smad1/5/9 pathway, with no apparent effect on other cell types. This reduction in OLs was associated with myelin degeneration, axonal damage, and impaired motor function. ConclusionThe study confirms BMP7's significant involvement in the pathophysiology of demyelinating diseases and supports its potential as a therapeutic target or biomarker. Future research should focus on therapeutic strategies to enhance BMP7 function and further investigate the mechanisms by which BMP7 supports myelin integrity.

Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive. The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice. We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in β-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice. These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.

Influence of bone morphogenetic protein (BMP) signaling and masticatory load on morphological alterations of the mouse mandible during postnatal development

ObjectiveBone homeostasis relies on several contributing factors, encompassing growth factors and mechanical stimuli. While bone morphogenetic protein (BMP) signaling is acknowledged for its essential role in skeletal development, its specific impact on mandibular morphogenesis remains unexplored. Here, we investigated the involvement of BMP signaling and mechanical loading through mastication in postnatal mandibular morphogenesis. DesignWe employed conditional deletion of Bmpr1a in osteoblasts and chondrocytes via Osterix-Cre. Cre activity was induced at birth for the 3-week group and at three weeks for the 9-week and 12-week groups, respectively. The conditional knockout (cKO) and control mice were given either a regular diet (hard diet, HD) or a powdered diet (soft diet, SD) from 3 weeks until sample collection, followed by micro-CT and histological analysis. ResultsThe cKO mice exhibited shorter anterior lengths and a posteriorly inclined ramus across all age groups compared to the control mice. The cKO mice displayed an enlarged hypertrophic cartilage area along with fewer osteoclast numbers in the subchondral bone of the condyle compared to the control group at three weeks, followed by a reduction in the cartilage area in the posterior region at twelve weeks. Superimposed imaging and histomorphometrical analysis of the condyle revealed that BMP signaling primarily affects the posterior part of the condyle, while mastication affects the anterior part. ConclusionsUsing 3D landmark-based geometric morphometrics and histological assessments of the mandible, we demonstrated that BMP signaling and mechanical loading reciprocally contribute to the morphological alterations of the mandible and condyle during postnatal development.

Development of multi-layered three-dimensional printed scaffold for sequential delivery of biomolecules

Spatiotemporal control of exogenous growth factors plays a crucial role in the sequential repair of damaged tissues. However, traditional therapeutic trials have mostly relied on the delivery of a single molecule because of the limitations of rapid diffusion and the instability of biomolecules. In this study, we developed a novel strategy using a composite of gelatin and silica as an alternative for the stable and sequential release of biomolecules. Two biomolecules, basic fibroblast growth factor and bone morphogenetic protein-2, were incorporated into two separate composites and sequentially layered onto the activated polymer surface. Each molecule was sequentially released from each layer of the scaffold and the silica composite prevented rapid diffusion owing to its nano-porous structure. The adhesion, proliferation, and osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells were significantly enhanced in the double-layered group containing separately delivered dual molecules compared with the control or single groups. Our developed gelatin&amp;ndash;silica composite was successfully placed in double layers on polymer scaffolds, and cellular responses were promoted in this manner. These results demonstrated that our scaffolding system has potential as a therapeutic strategy for the delivery of dual or multiple biomolecules in regenerative medicine. &amp;nbsp;

Polystyrene nanoplastics mediate skeletal toxicity through oxidative stress and the BMP pathway in zebrafish (Danio rerio)

The widespread presence of micro(nano)plastics (MNPs) has generated public concern. Studies have indicated that MNPs can accumulate in mammalian bones; however, research on the skeletal toxicity and underlying molecular mechanisms of MNPs in aquatic organisms remains limited. We subjected zebrafish embryos to three varying levels (1, 10, 100 μg/mL) of polystyrene nanoplastics (PSNPs) exposure over a period of 7 days in our research. The results revealed that PSNPs significantly reduced the body length and hatching rate of zebrafish, leading to skeletal deformities. mRNA level analysis showed significant upregulation of sp7, sparc, and smad1 genes transcription by PSNPs. Moreover, PSNPs markedly downregulated the mRNA levels associated with runx2a, bmp2a, and bmp4. Further investigations demonstrated that PSNPs dramatically increased ROS levels in zebrafish larvae, with significant downregulation of transcription levels of sod1 and cat genes, resulting in a sharp increase in transcription levels of apoptosis-related regulatory genes bcl-2 and bax. Furthermore, PSNPs led to a marked rise in Caspase 3 activity in zebrafish larvae, suggesting the initiation of apoptosis. PSNPs also notably inhibited alkaline phosphatase (AKP) activity. Compared to a 4-day exposure, a 7-day exposure to PSNPs intensified abnormalities across multiple indicators. In summary, our research indicates that PSNPs cause significant oxidative stress in zebrafish larvae, resulting in apoptosis. Moreover, PSNPs disrupt the transcription of genes related to skeletal development through the bone morphogenetic protein (BMP) pathway, further disrupting skeletal development processes and ultimately resulting in skeletal deformities in zebrafish larvae. This study provides new insights into the skeletal toxicity of MNPs.

Bone graft substitutes used in anterior lumbar interbody fusion: a contemporary systematic review of fusion rates and complications.

Anterior lumbar interbody fusion (ALIF) uses a broad-footprint interbody cage designed to maximize fusion rates for treating degenerative disc disease. Bone graft substitutes are being increasingly utilized during ALIF to replace or supplement autologous iliac crest bone grafts. This approach aims to optimize fusion efficacy while minimizing associated postoperative complications. The objective of this systematic review was to examine recent studies on fusion rates and postoperative complications associated with bone graft substitutes used in ALIF. We conducted a systematic review of the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, MEDLINE, and PubMed databases, to critically examine a decade of research (January 1, 2012, to July 6, 2023) on the effectiveness and safety of various bone graft substitutes in ALIF. This timeframe was chosen to build on a previous systematic review published in 2013. The PRISMA guidelines were used. In total, 27 articles met our stringent inclusion and exclusion criteria. A substantial portion of these studies (67%) focused on recombinant human bone morphogenetic protein-2 (rhBMP-2) and highlighted its efficacy for achieving high fusion rates. However, the literature presents a dichotomy regarding the association of rhBMP-2 with increased postoperative complications. Notably, the methodologies for evaluating spinal fusion varied across studies. Only one-third of studies employed computed tomography to assess interbody fusion at 12 months postoperatively, highlighting the urgent need to establish uniform fusion criteria to facilitate more accurate comparative analyses. Moreover, there was considerable variability in the criteria used for diagnosing and detecting postoperative complications, significantly influencing the reported incidence rates. This review underscores the need for continued research into bone graft substitutes, particularly focusing on assessment of long-term complications. Future research endeavors should concentrate on developing comprehensive clinical guidelines to aid in the selection of the most suitable bone graft substitutes for use in ALIF, thereby enhancing patient outcomes and surgical efficacy.