Search Results (129)

Decellularized tissue scaffolds mimic the native pulp-dentin microenvironment and support the odontogenic development of stem cells. This study investigated the dentinogenic effect of Wharton’s Jelly Mesenchymal Stem Cells (WJMSCs) in decellularized human dental pulp (DHDP) with bone morphogenic protein-7 (BMP-7) at three concentrations: 0 ng/mL (control), 25 ng/mL, and 50 ng/mL. The effects of BMP-7 were evaluated by histological examination, WJMSC viability using AlamarBlue, dentinogenic gene expression by qPCR, and dentinogenic protein expression by ELISA. By day 21, all three groups exhibited cell distribution along the pore surfaces of DHDP, followed by the presence of a collagen matrix in the tissue. WJMSC viability treated with 25 ng/mL and 50 ng/mL showed a statistically significant increase on days 7, 14, and 21 compared to the control group (p < 0.05). Gene expression analysis of dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1), and odontogenic marker (Runx2) revealed 25 ng/mL BMP-7 resulted in significantly higher expression levels for DMP-1 and Runx2 on day 21 compared to control and 50 ng/mL BMP-7 group (p < 0.05). DSPP and DMP-1 protein expressions also showed trends similar to those of gene expressions. BMP-7 (25 ng/mL) can maintain cell viability and promote dentinogenic effects of WJMSC in the DHDP scaffold. Full article

Male sex and aging are risk factors for fibro-calcific aortic valve disease (FCAVD), indicating an understudied influence of sex hormones. Valvular interstitial cells (VICs) from female and male donors were isolated and exposed to pro-calcifying medium (PM), and the expression of matrix gla protein (MGP), fibronectin (FN1) and bone morphogenic protein 2 (BMP2) was analyzed. The effect of sex hormones on hydroxyapatite (HA) deposition by VICs was also analyzed. Exposure to PM increased MGP gene expression in male (n = 5, +5.8-fold, p = 0.031), and female VICs (n = 6, +4.9-fold, p = 0.004). In female VICs a +3.5-fold MGP increase accompanied the transition from the fibrotic to the calcific phase (p = 0.022 vs. males) while in male VICs the increase was delayed to the calcific phase. Female VICs upregulated FN1 (+1.8-fold, p = 0.003), while male VICs upregulated BMP2 (+3.7-fold, p = 0.05). 5α-dihydrotestosterone increased HA deposition +6.3-fold in male and +5.2-fold in female VICs (p ≤ 0.001 and p < 0.04, respectively). It further decreased BMP2 (p < 0.001) in male VICs and increased MGP in female VICs (p = 0.087). Female VICs decreased HA deposition when exposed to progesterone (−2.4-fold, p = 0.037 vs. PM) and estrogen (−2.0-fold, p = 0.072). In summary, VICs show donor-sex-specific gene expression which is modifiable by 5α-dihydrotestosterone. This needs to be considered when designing in vitro regulatory studies. Full article

Corneal fibrosis, a significant source of visual impairment, can result from keratocyte-to-myofibroblast transdifferentiation during wound healing. This study investigated the antifibrotic role of 1,25-dihydroxyvitamin D₃ (1,25 Vit D) and the lesser-known vitamin D, 24,25-dihydroxyvitamin D₃ (24,25 Vit D), in human and mouse corneal stromal cells (HSCs and MSCs) and in a Vit D receptor knockout (VDR KO) mouse model. Cells were treated with TGF-β1 ± Vit D metabolites and the expression of fibrotic and antifibrotic genes and proteins was evaluated. Both metabolites significantly reduced α-smooth muscle actin levels in HSCs, MSCs and organ-cultured mouse corneas (p < 0.05). They also upregulated the mRNA expression of BMP2, BMP6, BMPR2, and TGF-β3, as well as the protein expression of BMP6 and TGF-β3. VDR KO corneas subjected to alkali injury exhibited increased fibrotic responses and reduced CD45+ immune cell infiltration compared to wild-type controls. Notably, 24,25 Vit D exerted antifibrotic effects even in VDR KO cells, and the alternative 24,25 Vit D receptor FAM57B was expressed in all corneal cell layers. These results reveal consistent antifibrotic effects of both 1,25 and 24,25 Vit D across species, support the existence of VDR-independent mechanisms in the cornea, and offer new insights into potential therapeutic strategies for preventing corneal fibrosis. Full article

Synthetic biomaterials are widely used as bone graft substitutes, but their osteogenic capacity is limited as they lack osteogenic growth factors. This study aimed to enhance the osteogenesis of a novel hydroxyapatite/aragonite (HAA) biomaterial by incorporating decellularized bone matrix and bone morphogenetic protein (BMP)-2 and BMP-7 (BMP-2/7). Human umbilical mesenchymal stem cells (MSCs) were able to proliferate and differentiate on HAA. HEK-293T cells exogenously expressing BMP-2/7 successfully secreted BMP-2/7, which was assessed by enzyme-linked immunosorbent assay. By establishing a co-culture of MSCs with HEK-293T cells expressing BMP-2/7, we successfully created an artificial allograft that integrates both synthetic biomaterials and functional organic components, offering the potential to enhance osteogenesis. The decellularized (by freeze/thawing) functional HAA was implanted between the tibia and anterior tibialis muscle in murine models and assessed the induced bone formation via micro-computer tomography, histology, and osteogenic markers mRNA expression by a reverse transcription-quantitative polymerase chain reaction. A significant increase in new bone formation was seen in the functional HAA implanted group. In conclusion, this study revealed that bone formation following the HAA implantation can be enhanced by a functional decellularized matrix, comprising BMP-2/7, via in vitro tissue engineering using MSCs and HEK-293T cells expressing BMP-2/7. Full article

Sotatercept selectively binds free activins and growth differentiation factors by reproducing the binding domain of the activin receptor type IIA (ACTRIIA). The sequester of activins blunts the downstream signaling pathway, resulting in the reactivation of the bone morphogenic protein (BMP) receptor type 2 signaling and inhibition of pathological remodeling in pulmonary circulation. The balance between proliferative and antiproliferative pathways is restored, with a favorable impact on the progression of pulmonary arterial hypertension (PAH). Sotatercept, first approved for the treatment of hematological disorders such as anemia, has recently received approval as a drug in the treatment of group 1 PAH, either in United States or Europe. In this review, we will discuss the application of sotatercept and its cross reactivity in function alone or in combination with other drugs currently used for PAH. We will try also to further discuss what is known regarding the hematological effects of sotatercept, both from preclinical and clinical studies points of view, since they are the root of the side effects seen in PAH trials, such as bleeding and increased hemoglobin. Full article

Biodentine, a tricalcium silicate cement, has emerged as a retrograde root-end filling material to promote periapical lesion (PL) healing after apicoectomy. However, its underlying mechanisms remain unclear. This study tested the hypothesis that Biodentine stimulates the osteogenic differentiation of mesenchymal stromal cells (MSCs) derived from PLs. The Biodentine extract (B-Ex) was prepared by incubating polymerized Biodentine in RPMI medium (0.2 g/mL) for three days at 37 °C. B-Ex, containing both released microparticles and soluble components, was incubated with PL-MSCs cultured in either a basal MSC medium or suboptimal osteogenic medium. Osteogenic differentiation was assessed by Alizarin Red staining and the expression of 20 osteoblastogenesis-related genes. Non-cytotoxic concentrations of B-Ex stimulated the proliferation of PL-MSCs and induced their osteogenic differentiation in a dose-dependent manner, with a significantly enhanced effect in suboptimal osteogenic medium. B-Ex upregulated most early and late osteoblastic genes. However, the differentiation process was prolonged, as indicated by the delayed expression of wingless-type MMTV integration site family member 2 (WNT2), bone gamma-carboxyglutamate protein (BGLAP), bone morphogenic protein-2 (BMP-2), growth hormone receptor (GHR), and FOS-like 2, AP-1 transcription factor subunit (FOSL2), compared with their expression under optimal osteogenic conditions. The stimulatory effect of B-Ex was primarily calcium dependent, as it was reduced by 85% when B-Ex was treated with the calcium-chelating agent EGTA. In conclusion, Biodentine promotes the osteogenic differentiation of PL-MSCs in a calcium-dependent manner, supporting its stimulatory role in periapical healing. Full article

Background/Objectives: Bioactive materials are gaining increased popularity as materials of choice for pulpal regeneration. A similar trend is emerging with root repair materials; however, there is a significant gap in the literature about cementogenic ability of bioceramic repair materials on the periodontal ligament cells. The aim of the present study was to investigate the effect of bioceramic materials (Biodentine and Bio-C Repair) on the cementogenesis potential of the periodontal ligament stem cells (PDLSCs). Methods: PDLSCs were isolated using the enzymatic digestion approach from sound extracted teeth. Material extracts were prepared on rubber discs and immersed in fresh growth medium for 24 h at 37 °C. Reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression levels of cementogenic markers cementum protein 1 (CEMP1), Cementum attachment protein (CAP), pathway markers transforming growth factor β1(TGF-β1), bone morphogenic protein 2 (BMP2), and inflammatory marker IL-6. Results: Both materials (Biodentine and Bio-C Repair) showed significantly higher gene expressions when compared to the control groups. The gene expression with Bio-C Repair significantly increased when compared with Biodentine, except for TGF-β1 expression, where both materials exhibited similar results. Conclusions: Bio-C Repair demonstrated increased gene expression of cementogenic markers compared to Biodentine under the tested conditions. Further in vivo studies are deemed necessary to translate the findings from this study into clinical practice. Full article

The aim of the present study was to test the sequential and simultaneous release of rhBMP2 and rhVEGF165 from poly-l-lysine-heparin (PLL-Hep) poly-electrolyte multilayer (PEM) coating on titanium surfaces for their ability to enhance peri-implant bone formation and CD31 expression around disc-shaped titanium implants (5 × 7 mm) in mini-pig mandibles. Bare titanium surfaces loaded with respective growth factor combinations served as controls. Ten different surface conditions were tested exhibiting early VEGF release, early BMP release, simultaneous VEGF and BMP release, and sole VEGF/BMP release, respectively. The implants were inserted press-fit into 5 mm trephine cavities at the lower border of the mandibles of mini-pigs and left to heal for 4 and 13 weeks. After 4 weeks, there was no significant difference in peri-implant bone formation, bone–implant contact nor CD31 expression between the different surface conditions. After 13 weeks, bone formation was significantly higher in the zone of 100 μm next to implant surfaces releasing either BMP alone or with an early release of BMP2. Expression of CD31 has significantly decreased from 4 to 13 weeks with significantly higher values in the group of implants with early release of BMP2. The results indicate that the range of released growth factors is limited to a distance of approximately 100 μm and that the sequence of early release of BMP2 followed by VEGF165 promotes peri-implant bone formation and peri-implant angiogenesis, which is in contrast to the current understanding of the temporal patterns of growth factor release for enhancement of bone formation. Full article

The metabolic poise, or balance, between glycolysis and fatty acid oxidation (FAO) has recently been found to play a critical role in osteogenic differentiation and homeostasis. While simulated microgravity (SMG) is known to impede osteoblast differentiation (OBD) by inhibiting the Wnt/β-catenin pathway, how it affects osteoblast metabolism in this context remains unclear. We previously analyzed the effect of SMG on the differentiation of pre-osteoblast MC3T3-E1 cells and found that it reduced focal adhesion kinase (FAK) activity. This, in turn, downregulated Wnt/β-catenin and two of its downstream targets critical for OBD bone morphogenic protein-2 (BMP2) and type-1 collagen (COL1) formation, leading to a reduction in alkaline phosphatase (ALP) activity and cell matrix mineralization. In this study, we further analyzed how SMG-induced alterations in energy metabolism contribute to the inhibition of OBD in MC3T3-E1 cells. Consistent with our earlier findings, we demonstrated that SMG inhibits OBD by downregulating the collective activity of FAK and the Wnt/β-catenin-BMP2-COL1 transcriptional pathway. Interestingly, we observed that SMG also reduces the abundance of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and carnitine palmitoyl transferase-1α (CPT1A), which are all key metabolic factors regulating mitochondrial number and FAO capacity. Accordingly, we found that the mitochondrial content and FAO potential of MC3T3-E1 cells were lower upon exposure to SMG but were both rescued upon administration of the FAK activator cytotoxic necrotizing factor-1 (CNF1), thereby allowing cells to overcome SMG-induced inhibition of OBD. Taken together, our study indicates that the metabolic regulator SIRT1 may be a new target for reversing SMG-induced bone loss. Full article

The temporomandibular joint (TMJ) is unique in both developmental origin and functional maintenance. The role of bone morphogenic protein (BMP) signaling in endochondral ossification has been widely investigated but not in the context of the TMJ. We employed a histomorphometric analysis approach to understand how augmented BMP signaling in the cranial neural crest affects the postnatal development of the TMJ. Our analysis showed that cartilage length in the mandibular condyle was reduced in Wnt1 Cre;caBmpr1a mice before the weaning stage (P17). However, following weaning, the mandibular condylar cartilage showed recovered length (P28 and P42). Furthermore, the changes in cartilage length coincide with alterations in cell death in the superficial region of the mandibular condyle. These results suggest that BMP signaling influences chondrocyte cell death and TMJ development in a timepoint-specific manner. Full article

Background: Alveolar bone reconstruction with recombinant protein has several advantages, including less surgical timing, and reduced infection. This systematic review aims to assess the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) as a treatment modality for children with cleft lip and palate compared to the conventional iliac crest bone grafting approach. Methods: For current systematic review and meta-analysis, five electronic databases, namely, MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Web of Science, and ScienceDirect, were searched. The primary outcome measured in this review was bone volume and height after alveolar bone reconstruction surgery. The Risk of Bias Tool 2 assessed the risk of bias for randomized control trials and the Risk of Bias tool for non-randomized trials of interventions for non-randomized studies. By evaluating pooled meta-analysis, the mean difference was calculated. GRADE uncertainty of evidence was performed to assess the certainty of the results. Results: Of 230 identified studies, 6 randomized and 2 non-randomized studies were included in the current review. The average bone volume was higher among the rhBMP-2 group at 61.11% ± 24.6% than the iliac crest group at 59.12% ± 18.59%. The calculated mean bone height was higher in the iliac crest group at 78.65% ± 14.38% than in the rhBMP-2 group at 67.5% ± 5.45%. The risk of bias reported in the studies was low to moderate. The result of the meta-analysis supported using rhBMP-2 in alveolar bone reconstruction; however, no significant association was found (mean difference: −1.24; confidence interval: −4.14 to 1.67). Conclusions: The calculated meta-analysis reported no significant difference, and the quality of evidence measured was also moderate. Hence, more clinical trials are required to support using rhBMP-2 as an alternative to traditional techniques for treating cleft lip and palate. Full article

Background: Peripheral arterial disease (PAD) is known to be strongly linked to major adverse limb events, ultimately leading to an increased risk of limb-threatening conditions. We developed a predictive model using five identified biomarkers to predict major adverse limb events, limb loss, diabetic (DM) foot ulcers, and vascular intervention in patients with underlying PAD and DM over 2 years. Methods: A single-center prospective case control study with was conducted with 2 years’ follow up. In the discovery phase the cohort was randomly split into a 70:30 ratio, and proteins with a higher mean level of expression in the DM PAD group compared to the DM non-PAD group were identified. Next, a random forest model was trained using (1) clinical characteristics, (2) a five-protein panel, and (3) clinical characteristics combined with the five-protein panel. Demographic data were analyzed by independent t-test and chi-square test. The importance of predictive features was calculated using the variable importance (gain) score. The model was used and assessed for its ability to diagnose PAD, predict limb loss, predict major adverse limb events (MALEs), predict diabetic foot ulcers, and predict the need for vascular surgery. The model was evaluated using area under the receiver operating characteristic curve and net reclassification index. Results: The cohort of 392 patients was matched for age, sex, and comorbidities. Five proteins were identified (TNFa: tumor necrosis factor alpha, BMP-10: bone morphogenic protein 10, CCL15/MIP1 delta: chemokine (c-c motif) ligand 15/macrophage inflammatory protein 1 delta, MMP-10: matrix metalloprotease 10, and HTRA2/Omi: HTRA2, also known as Omi) as having a significantly higher level of expression in the DM PAD group. HTRA/Omi had the highest contribution to the model’s ability to diagnose PAD in diabetic patients. Model performance was best when combined with clinical characteristics to predict limb loss (AUROC 0.86, 0.76, 0.80), foot ulcer (AUROC 0.87, 0.82, 0.67), MALE (AUROC 0.81, 0.78, 0.67), and the need for vascular surgery (AUROC 0.82, 0.81, 0.61). Conclusions: In this study, we describe a biomarker panel that can be used in combination with clinical characteristics to create an accurate prediction model for diagnosis and prognostication of PAD in the setting of DM. Full article

Background: Vascular calcification (VC) is a dynamic, tightly regulated process driven by cellular activity and resembling the mechanisms of bone formation, with specific molecules playing pivotal roles in its progression. We aimed to investigate the involvement of the bone morphogenic proteins (BMP-2, BMP-4, BMPR-1a/1b, and BMPR-2) system in this process. Our study used an advanced in vitro model that simulates the biological environment of the vascular wall, assessing the ability of a phosphate mixture to induce the osteoblastic switch in human coronary artery smooth muscle cells (HCASMCs). Methods: HCASMCs were grown in mono- and co-culture with human coronary artery endothelial cells (HCAECs) in a double-flow bioreactor (LiveBox2 and IVTech), allowing static and dynamic conditions through a peristaltic pump. The VC was stimulated by incubation in a calcifying medium for 7 days. A BMP system Real-Time PCR was performed at the end of each experiment. Results: In monocultures, BMP-2 expression increased in calcified HCASMCs in static (p = 0.01) and dynamic conditions. BMP-4 and the biological receptors were expressed in all the experimental settings, increasing mainly in dynamic flow conditions. In co-cultures, we observed a marked increase in BMP-2 and BMP-4, BMPR-1a (p = 0.04 and p = 0.01, respectively), and BMPR-2 (p = 0.001) in the calcifying setting mostly in dynamic conditions. Conclusions: The increase in BMP-2/4 in co-culture suggests that these genes might promote the switch towards an osteogenic-like phenotype, data also supported by the rise of both BMPR-1a and BMPR-2. Thus, our findings provide insights into the mechanisms by which dynamic co-culture modulates the BMP system activation in an environment mimicking in vivo VC’s cellular and mechanical characteristics. Full article

Sotatercept acts as a type IIA-Fc activin receptor, thereby scavenging free activin from its physiological membrane receptor. Through this type of action, sotaterpect leads to a rebalancing of the proliferation and antiproliferation pathways of pulmonary smooth muscle cells in response to bone morphogenic protein (BMP). Although sotatercept has been approved as the fourth pillar of therapy for group 1 pulmonary arterial hypertension (PAH) in the United States and Europe, several studies are ongoing to broaden the application of the drug to non-Group 1 PAH. We provide an overview of the clinical and preclinical evidence of targeting the activation pathway by sotatercept in the treatment of PAH. We also discuss other potential applications of sotatercept in the context of pulmonary hypertension other than PAH group 1. Full article

Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling, often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here, we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including imbalances in vasoconstrictor–vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neurostimulation including acupuncture. Lastly, we also touch upon the disease’s different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost. Full article