Divergent and Compensatory Effects of BMP2 and BMP4 on the VSMC Phenotype and BMP4's Role in Thoracic Aortic Aneurysm Development.

Vascular smooth muscle cells (VSMCs) play a key role in aortic aneurysm formation. Bone morphogenetic proteins (BMPs) have been implicated as important regulators of VSMC phenotype, and dysregulation of the BMP pathway has been shown to be associated with vascular diseases. The aim of this study was to investigate for the first time the effects of BMP-4 on the VSMC phenotype and to understand its role in the development of thoracic aortic aneurysms (TAAs). Using the angiotensin II (AngII) osmotic pump model in mice, aortas from mice with VSMC-specific BMP-4 deficiency showed changes similar to AngII-infused aortas, characterised by a loss of contractile markers, increased fibrosis, and activation of matrix metalloproteinase 9. When BMP-4 deficiency was combined with AngII infusion, there was a significantly higher rate of apoptosis and aortic dilatation. In vitro, VSMCs with mRNA silencing of BMP-4 displayed a dedifferentiated phenotype with activated canonical BMP signalling. In contrast, BMP-2-deficient VSMCs exhibited the opposite phenotype. The compensatory regulation between BMP-2 and BMP-4, with BMP-4 promoting the contractile phenotype, appeared to be independent of the canonical signalling pathway. Taken together, these results demonstrate the impact of VSMC-specific BMP-4 deficiency on TAA development.

Mesenchymal Stem Cell Exosomes Enhance Posterolateral Spinal Fusion in a Rat Model.

Spinal fusion, a common surgery performed for degenerative lumbar conditions, often uses recombinant human bone morphogenetic protein 2 (rhBMP-2) that is associated with adverse effects. Mesenchymal stromal/stem cells (MSCs) and their extracellular vesicles (EVs), particularly exosomes, have demonstrated efficacy in bone and cartilage repair. However, the efficacy of MSC exosomes in spinal fusion remains to be ascertained. This study investigates the fusion efficacy of MSC exosomes delivered via an absorbable collagen sponge packed in a poly Ɛ-caprolactone tricalcium phosphate (PCL-TCP) scaffold in a rat posterolateral spinal fusion model. Herein, it is shown that a single implantation of exosome-supplemented collagen sponge packed in PCL-TCP scaffold enhanced spinal fusion and improved mechanical stability by inducing bone formation and bridging between the transverse processes, as evidenced by significant improvements in fusion score and rate, bone structural parameters, histology, stiffness, and range of motion. This study demonstrates for the first time that MSC exosomes promote bone formation to enhance spinal fusion and mechanical stability in a rat model, supporting its translational potential for application in spinal fusion.

BMP Stimulation Differentially Affects Phosphorylation and Protein Stability of ß-Catenin in Breast Cancer Cell Lines.

Increased expression and nuclear translocation of ß-CATENIN is frequently observed in breast cancer, and it correlates with poor prognosis. Current treatment strategies targeting ß-CATENIN are not as efficient as desired. Therefore, detailed understanding of ß-CATENIN regulation is crucial. Bone morphogenetic proteins (BMP) and Wingless/Integrated (WNT) pathway crosstalk is well-studied for many cancer types including colorectal cancer, whereas it is still poorly understood for breast cancer. Analysis of breast cancer patient data revealed that BMP2 and BMP6 were significantly downregulated in tumors. Since mutation frequency in genes enhancing ß-CATENIN protein stability is relatively low in breast cancer, we aimed to investigate whether decreased BMP ligand expression could contribute to a high protein level of ß-CATENIN in breast cancer cells. We demonstrated that downstream of BMP stimulation, SMAD4 is required to reduce ß-CATENIN protein stability through the phosphorylation in MCF7 and T47D cells. Consequently, BMP stimulation reduces ß-CATENIN levels and prevents its nuclear translocation and target gene expression in MCF7 cells. Conversely, BMP stimulation has no effect on ß-CATENIN phosphorylation or stability in MDA-MB-231 and MDA-MB-468 cells. Likewise, SMAD4 modulation does not alter the response of those cells, indicating that SMAD4 alone is insufficient for BMP-induced ß-CATENIN phosphorylation. While our data suggest that considering BMP activity may serve as a prognostic marker for understanding ß-CATENIN accumulation risk, further investigation is needed to elucidate the differential responsiveness of breast cancer cell lines.

Bone Morphogenetic Protein 2 Enhances Porcine Beige Adipogenesis via AKT/mTOR and MAPK Signaling Pathways.

Bone morphogenetic protein 2 (BMP2) has been reported to regulate adipogenesis, but its role in porcine beige adipocyte formation remains unclear. Our data reveal that BMP2 is significantly induced at the early stages of porcine beige adipocyte differentiation. Additionally, supplementing rhBMP2 during the early stages, but not the late stages of differentiation, significantly enhances porcine SVF adipogenesis, thermogenesis, and proliferation. Furthermore, compared to the empty plasmid-transfected-SVFs, BMP2-overexpressed SVFs had the enhanced lipid accumulation and thermogenesis, while knockdown of BMP2 in SVFs exhibited the opposite effect. The RNA-seq of the above three types of cells revealed the enrichment of the annotation of thermogenesis, brown cell differentiation, etc. In addition, the analysis also highlights the significant enrichment of cell adhesion, the MAPK cascade, and PPARγ signaling. Mechanistically, BMP2 positively regulates the adipogenic and thermogenic capacities of porcine beige adipocytes by activating PPARγ expression through AKT/mTOR and MAPK signaling pathways.

Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

Tumor cell-intrinsic epigenetic SETpoint of cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) exhibit spatial and functional diversity. Here, Niu et al. unveil SETD2's function in lipid metabolism and CAF heterogeneity in pancreatic ductal adenocarcinoma. SETD2 deficiency boosts oxidative phosphorylation activity, prompting lipid-laden CAF formation through BMP2 signaling, offering promising therapeutic avenues in personalized cancer treatment.

RUNX1-BMP2 promotes vasculogenic mimicry in laryngeal squamous cell carcinoma via activation of the PI3K-AKT signaling pathway.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck. Vasculogenic mimicry (VM) is crucial for tumor growth and metastasis and refers to the formation of fluid channels by invasive tumor cells rather than endothelial cells. However, the regulatory mechanisms underlying VM during the malignant progression of LSCC remain largely unknown. METHODS: Gene expression and clinical data for LSCC were obtained from the TCGA and Gene GEO (GSE27020) databases. A risk prediction model associated with VM was established using LASSO and Cox regression analyses. Based on their risk scores, patients with LSCC were categorized into high- and low-risk groups. The disparities in immune infiltration, tumor mutational burden (TMB), and functional enrichment between these two groups were examined. The core genes in LSCC were identified using the machine learning (SVM-RFE) and WGCNA algorithms. Subsequently, the involvement of bone morphogenetic protein 2 (BMP2) in VM and metastasis was investigated both in vitro and in vivo. To elucidate the downstream signaling pathways regulated by BMP2, western blotting was performed. Additionally, ChIP experiments were employed to identify the key transcription factors responsible for modulating the expression of BMP2. RESULTS: We established a new precise prognostic model for LSCC related to VM based on three genes: BMP2, EPO, and AGPS. The ROC curves from both TCGA and GSE27020 validation cohorts demonstrated precision survival prediction capabilities, with the nomogram showing some net clinical benefit. Multiple algorithm analyses indicated BMP2 as a potential core gene. Further experiments suggested that BMP2 promotes VM and metastasis in LSCC. The malignant progression of LSCC is promoted by BMP2 via the activation of the PI3K-AKT signaling pathway, with the high expression of BMP2 in LSCC resulting from its transcriptional activation by runt-related transcription factor 1 (RUNX1). CONCLUSION: BMP2 predicts poor prognosis in LSCC, promotes LSCC VM and metastasis through the PI3K-AKT signaling pathway, and is transcriptionally regulated by RUNX1. BMP2 may be a novel, precise, diagnostic, and therapeutic biomarker of LSCC.

rhBMP-2 induces terminal differentiation of human bone marrow mesenchymal stromal cells only by synergizing with other signals.

BACKGROUND: Recombinant human bone morphogenetic protein 2 (rhBMP-2) and human bone marrow mesenchymal stromal cells (hBM-MSCs) have been thoroughly studied for research and translational bone regeneration purposes. rhBMP-2 induces bone formation in vivo, and hBM-MSCs are its target, bone-forming cells. In this article, we studied how rhBMP-2 drives the multilineage differentiation of hBM-MSCs both in vivo and in vitro. METHODS: rhBMP-2 and hBM-MSCs were tested in an in vivo subcutaneous implantation model to assess their ability to form mature bone and undergo multilineage differentiation. Then, the hBM-MSCs were treated in vitro with rhBMP-2 for short-term or long-term cell-culture periods, alone or in combination with osteogenic, adipogenic or chondrogenic media, aiming to determine the role of rhBMP-2 in these differentiation processes. RESULTS: The data indicate that hBM-MSCs respond to rhBMP-2 in the short term but fail to differentiate in long-term culture conditions; these cells overexpress the rhBMP-2 target genes DKK1, HEY-1 and SOST osteogenesis inhibitors. However, in combination with other differentiation signals, rhBMP-2 acts as a potentiator of multilineage differentiation, not only of osteogenesis but also of adipogenesis and chondrogenesis, both in vitro and in vivo. CONCLUSIONS: Altogether, our data indicate that rhBMP-2 alone is unable to induce in vitro osteogenic terminal differentiation of hBM-MSCs, but synergizes with other signals to potentiate multiple differentiation phenotypes. Therefore, rhBMP-2 triggers on hBM-MSCs different specific phenotype differentiation depending on the signalling environment.

Osteogenic Effects of the Diospyros lotus L. Leaf Extract on MC3T3-E1 Pre-Osteoblasts and Ovariectomized Mice via BMP2/4 and TGF ß Pathways.

Osteoporosis, a disease defined by the primary bone strength due to a low bone mineral density, is a bone disorder associated with increased mortality in the older adult population. Osteoporosis is mainly treated via hormone replacement therapy, bisphosphates, and anti-bone resorption agents. However, these agents exert severe side effects, necessitating the development of novel therapeutic agents. Many studies are focusing on osteogenic agents as they increase the bone density, which is essential for osteoporosis treatment. Here, we aimed to investigate the effects of Diospyros lotus L. leaf extract (DLE) and its components on osteoporosis in MC3T3-E1 pre-osteoblasts and ovariectomized mice and to elucidate the underlying related pathways. DLE enhanced the differentiation of MC3T3-E1 pre-osteoblasts, with a 1.5-fold elevation in ALP activity, and increased the levels of osteogenic molecules, RUNX family transcription factor 2, and osterix. This alteration resulted from the activation of bone morphogenic protein 2/4 (BMP2/4) and transformation of growth factor ß (TGF ß) pathways. In ovariectomized mice, DLE suppressed the decrease in bone mineral density by 50% and improved the expression of other bone markers, which was confirmed by the 3~40-fold increase in osteogenic proteins and mRNA expression levels in bone marrow cells. The three major compounds identified in DLE exhibited osteogenic and estrogenic activities with their aglycones, as previously reported. Among the major compounds, myricitrin alone was not as strong as whole DLE with all its constituents. The osteogenic activity of DLE was partially suppressed by the inhibitor of estrogen signaling, indicating that the estrogenic activity of DLE participated in its osteogenic activity. Overall, DLE suppresses osteoporosis by inducing osteoblast differentiation.

The role of the Piezo1 channel in osteoblasts under cyclic stretching: A study on osteogenic and osteoclast factors.

OBJECTIVES: Orthodontic tooth movement is a mechanobiological reaction induced by appropriate forces, including bone remodeling. The mechanosensitive Piezo channels have been shown to contribute to bone remodeling. However, information about the pathways through which Piezo channels affects osteoblasts remains limited. Thus, we aimed to investigate the influence of Piezo1 on the osteogenic and osteoclast factors in osteoblasts under mechanical load. MATERIALS AND METHODS: Cyclic stretch (CS) experiments on MC3T3-E1 were conducted using a BioDynamic mechanical stretching device. The Piezo1 channel blocker GsMTx4 and the Piezo1 channel agonist Yoda1 were used 12 h before the application of CS. MC3T3-E1 cells were then subjected to 15% CS, and the expression of Piezo1, Piezo2, BMP-2, OCN, Runx2, RANKL, p-p65/p65, and ALP was measured using quantitative real-time polymerase chain reaction, western blot, alkaline phosphatase staining, and immunofluorescence staining. RESULTS: CS of 15% induced the highest expression of Piezo channel and osteoblast factors. Yoda1 significantly increased the CS-upregulated expression of Piezo1 and ALP activity but not Piezo2 and RANKL. GsMTx4 downregulated the CS-upregulated expression of Piezo1, Piezo2, Runx2, OCN, p-65/65, and ALP activity but could not completely reduce CS-upregulated BMP-2. CONCLUSIONS: The appropriate force is more suitable for promoting osteogenic differentiation in MC3T3-E1. The Piezo1 channel participates in osteogenic differentiation of osteoblasts through its influence on the expression of osteogenic factors like BMP-2, Runx2, and OCN and is involved in regulating osteoclasts by influencing phosphorylated p65. These results provide a foundation for further exploration of osteoblast function in orthodontic tooth movement.

Biomimetic peroxidase MOF-Fe promotes bone defect repair by inhibiting TfR2 and activating the BMP2 pathway.

BACKGROUND: Large bone defects pose a clinical treatment challenge; inhibiting transferrin receptor 2 (TfR2), which is involved in iron metabolism, can promote osteogenesis. Iron-based metal-organic frameworks (MOF-Fe) particles not only inhibit TfR2 but also serve as biomimetic catalysts to remove hydrogen peroxide in reactive oxygen species (ROS); excess ROS can disrupt the normal functions of osteoblasts, thereby hindering bone regeneration. This study explored the potential effects of MOF-Fe in increasing osteogenic activity and clearing ROS. METHODS: In vitro experiments were performed to investigate the osteogenic effects of MOF-Fe particles and assess their impact on cellular ROS levels. To further validate the role of MOF-Fe in promoting bone defect repair, we injected MOF-Fe suspensions into the femoral defects of SD rats and implanted MOF-Fe-containing hydrogel scaffolds in rabbit cranial defect models and observed their effects on bone healing. RESULTS: In vitro, the presence of MOF-Fe significantly increased the expression levels of osteogenesis-related genes and proteins compared to those in the control group. Additionally, compared to those in the untreated control group, the cells treated with MOF-Fe exhibited a significantly increased ability to remove hydrogen peroxide from ROS and generate oxygen and water within the physiological pH range. In vivo experiments further confirmed the positive effect of MOF-Fe in promoting bone defect repair. CONCLUSION: This study supports the application of MOF-Fe as an agent for bone regeneration, particularly for mitigating ROS and activating the bone morphogenetic protein (BMP) pathway, demonstrating its potential value.

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signalling.

Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for neuronal computation1,2. Deviations from a balanced state have been linked to neurodevelopmental disorders, and severe disruptions result in epilepsy3-5. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here we identify a signalling pathway in the adult mouse neocortex that is activated in response to increased neuronal network activity. Overactivation of excitatory neurons is signalled to the network through an increase in the levels of BMP2, a growth factor that is well known for its role as a morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of perineuronal nets. PV-interneuron-specific disruption of BMP2-SMAD1 signalling is accompanied by a loss of glutamatergic innervation in PV cells, underdeveloped perineuronal nets and decreased excitability. Ultimately, this impairment of the functional recruitment of PV interneurons disrupts the cortical excitation-inhibition balance, with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signalling is repurposed to stabilize cortical networks in the adult mammalian brain.

Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment.

Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remain unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status - notably, obstructed fatty acid transportation - was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of BMP2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.

Effects of aflatoxin and fumonisin on gene expression of growth factors and inflammation-related genes in a human hepatocyte cell line.

Aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are mycotoxins widely distributed in maize and maized-based products, often occurring together. The implications of co-exposure to aflatoxin and fumonsin for human health are numerous, but a particular concern is the potential of FB1 to modulate AFB1 hepatotoxicity. This study evaluated the toxicity of these mycotoxins, alone or combined, in a human non-tumorigenic liver cell line, HHL-16 cells, and assessed the effects of AFB1 and FB1 on expression of genes involved in immune and growth factor pathways. The results demonstrated that in HHL-16 cells, both AFB1 and FB1 had dose-dependent and time-dependent toxicity, and the combination of them showed a synergistic toxicity in the cells. Moreover, AFB1 caused upregulation of IL6, CCL20, and BMP2, and downregulation of NDP. In combination of AFB1 with FB1, gene expression levels of IL6 and BMP2 were significantly higher compared to individual FB1 treatment, and had a tendency to be higher than individual AFB1 treatment. This study shows that FB1 may increase the hepatoxicity of AFB1 through increasing the inflammatory response and disrupting cell growth pathways.

miR-539-5p targets BMP2 to regulate Treg activation in B-cell acute lymphoblastic leukemia through TGF-ß/Smads/MAPK.

MicroRNAs (mRNAs) were believed to play an important role in cancers, and this study aimed to explore the mechanism of miRNA regulating Treg in B-cell acute lymphoblastic leukemia (B-ALL). Firstly, the differentially expressed miRNAs and target genes significantly associated with Tregs were screened out by high-throughput sequencing, and their enrichment pathways were analyzed. The binding relationship between miRNA and target genes was further verified, and the effects of miRNA on the proliferation and apoptosis of B-ALL Nalm-6 cells and Treg activation were analyzed. Results showed that differentially expressed miR-539-5p was significantly under-expressed, and its target gene BMP2 was significantly over-expressed in B-ALL, and significantly enriched in the TGF-ß1 pathway. In addition, both miR-539-5p and BMP2 were significantly correlated with Treg activity in B-ALL. In vitro experiments further confirmed that miR-539-5p could directly target BMP2. The low expression of miR-539-5p in B-ALL significantly promoted BMP2 expression to promote the proliferation and inhibit apoptosis of Nalm-6 cells. Furthermore, the high expression of BMP2 in B-ALL could cooperate with TGF-ß1 to promote the activation of human CD4+CD25-T cells to Treg, and significantly activate the TGF-ß/Smads/MAPK pathway. In vivo experiments also confirmed that overexpression of miR-539-5p significantly inhibited BMP2 to suppress Treg activation and Smad1 and Smad2 phosphorylation, and finally inhibit the B-ALL process. In conclusion, miR-539-5p was significantly under-expressed in B-ALL and could target BMP2 to promote its expression, and the overexpressed BMP2 further promoted Treg activation in B-ALL by regulating TGF-ß/Smads/MAPK pathway.

Noggin promotes osteogenesis in human adipose-derived mesenchymal stem cells via FGFR2/Src/Akt and ERK signaling pathway.

The balance between Noggin and bone morphogenetic proteins (BMPs) is important during early development and skeletal regenerative therapies. Noggin binds BMPs in the extracellular space, thereby preventing BMP signaling. However, Noggin may affect cell response not necessarily through the modulation of BMP signaling, raising the possibility of direct Noggin signaling through yet unspecified receptors. Here we show that in osteogenic cultures of adipose-derived stem cells (ASCs), Noggin activates fibroblast growth factor receptors (FGFRs), Src/Akt and ERK kinases, and it stabilizes TAZ proteins in the presence of dexamethasone. Overall, this leads ASCs to increased expression of osteogenic markers and robust mineral deposition. Our results also indicate that Noggin can induce osteogenic genes expression in normal human bone marrow stem cells and alkaline phosphatase activity in normal human dental pulp stem cells. Besides, Noggin can specifically activate FGFR2 in osteosarcoma cells. We believe our findings open new research avenues to further explore the involvement of Noggin in cell fate modulation by FGFR2/Src/Akt/ERK signaling and potential applications of Noggin in bone regenerative therapies.

Transpedicular injection of rhBMP-2 with ß-tricalcium phosphate to reduce the proximal junctional kyphosis after adult spinal deformity correction: preliminary study.

The aim of this preliminary study was to assess the impact of injecting recombinant human bone morphogenetic protein-2 (rhBMP-2) with ß-tricalcium phosphate (ß-TCP) carrier into the uppermost instrumented vertebra (UIV) during surgery to prevent the development of proximal junctional kyphosis (PJK) and proximal junctional failure (PJF). The 25 patients from study group had received 0.5 mg rhBMP-2 mixed with 1.5 g ß-TCP paste injection into the UIV during surgery. The control group consisted of 75 patients who underwent surgery immediately before the start of the study. The incidences of PJK and PJF were analyzed as primary outcomes. Spinopelvic parameters and patient-reported outcomes were analyzed as secondary outcomes. Hounsfield unit (HU) measurements were performed to confirm the effect of rhBMP-2 with ß-TCP on bone formation at preoperative and postoperative at computed tomography. PJK and PJF was more occurred in control group than study group (p = 0.02, 0.29, respectively). The HU of the UIV significantly increased 6 months after surgery. And the increment at the UIV was also significantly greater than that at the UIV-1 6 months after surgery. Injection of rhBMP-2 with ß-TCP into the UIV reduced PJK and PJF rates 6 months after surgery with new bone formation.

Recombinant Human Peptide Growth Factors, Bone Morphogenetic Protein-7 (rhBMP7), and Platelet-Derived Growth Factor-BB (rhPDGF-BB) for Osteoporosis Treatment in an Oophorectomized Rat Model.

Bone morphogenetic protein (BMP) and platelet-derived growth factor (PDGF) are known to regulate/stimulate osteogenesis, playing vital roles in bone homeostasis, rendering them strong candidates for osteoporosis treatment. We evaluated the effects of recombinant human BMP-7 (rhBMP7) and PDGF-BB (rhPDGF-BB) in an oophorectomy-induced osteoporosis rat model. Forty Sprague Dawley rats underwent oophorectomy surgery; treatments commenced on the 100th day post-surgery when all animals exhibited signs of osteoporosis. These peptide growth factors were administered intraocularly (iv) once or twice a week and the animals were monitored for a total of five weeks. Two weeks after the conclusion of the treatments, the animals were euthanized and tissues were collected for assessment of alkaline phosphatase, X-ray, micro-CT, and histology. The results indicate that the most promising treatments were 20 µg/kg rhPDGF-BB + 30 µg/kg rhBMP-7 twice a week and 30 µg/kg BMP-7 twice a week, showing significant increases of 15% (p < 0.05) and 13% (p < 0.05) in bone volume fraction and 21% (p < 0.05) and 23% (p < 0.05) in trabecular number, respectively. In conclusion, rhPDGF-BB and rhBMP-7 have demonstrated the ability to increase bone volume and density in this osteoporotic animal model, establishing them as potential candidates for osteoporosis treatment.

BMP2-ERK-ATF4 Axis-Based 6-methoxybenzofuran Compound I-9 Acts as Candidate Drug for Bone Formation and Anti-Osteoporosis.

As the global population ages, the number of patients with osteoporosis is rapidly rising. The existing first-line clinical drugs are bone resorption inhibitors that have difficulty restoring the bone mass of elderly patients to the safe range. The range and period of use of existing peptides and monoclonal antibodies are limited, and small-molecule bone formation-promoting drugs are urgently required. We established an I-9 synthesis route with high yield, simple operation, and low cost that was suitable for future large-scale production. I-9 administration promoted bone formation and increased bone mass in mice with low bone mass in an aged C57 mouse model. Our findings revealed a hitherto undescribed pathway involving the BMP2-ERK-ATF4 axis that promotes osteoblast differentiation; I-9 has favorable biosafety in mice. This study systematically investigated the efficacy, safety, and mechanism of I-9 for treating osteoporosis and positions this drug for preclinical research in the future. Thus, this study has promoted the development of small-molecule bone-promoting drugs.

The Evolution and Application of a Novel DNA Aptamer Targeting Bone Morphogenetic Protein 2 for Bone Regeneration.

Recombinant human bone morphogenetic protein 2 (rhBMP-2) is an FDA-approved growth factor for bone regeneration and repair in medical practice. The therapeutic effects of rhBMP-2 may be enhanced through specific binding to extracellular matrix (ECM)-like scaffolds. Here, we report the selection of a novel rhBMP-2-specific DNA aptamer, functionalization of the aptamer in an ECM-like scaffold, and its application in a cellular context. A DNA aptamer BA1 was evolved and shown to have high affinity and specificity to rhBMP-2. A molecular docking model demonstrated that BA1 was probably bound to rhBMP-2 at its heparin-binding domain, as verified with experimental competitive binding assays. The BA1 aptamer was used to functionalize a type I collagen scaffold, and fraction ratios were optimized to mimic the natural ECM. Studies in the myoblast cell model C2C12 showed that the aptamer-enhanced scaffold could specifically augment the osteo-inductive function of rhBMP-2 in vitro. This aptamer-functionalized scaffold may have value in enhancing rhBMP-2-mediated bone regeneration.