Teleost bone morphogenetic protein 2 (BMP2): Dynamic responses to infection and negative feedback regulation of inflammatory cytokines in gills of flounder (Paralichthys olivaceus).

Various signaling pathways are linked with osteogenesis and osteoarthritis progression. Bone Morphogenetic Protein 2 (BMP2), a key regulator within the TGF-β superfamily, is central to skeletal development through its ability to guide mesenchymal stem cells (MSCs) toward osteogenic and chondrogenic lineages. By activating canonical SMAD1/5/8 cascades alongside non-canonical MAPK branches (ERK, p38, JNK), BMP2 enhances transcriptional programs such as Runx2, thereby stimulating extracellular matrix synthesis, bone regeneration, and cartilage differentiation. Recombinant BMP2 (rhBMP2) has thus found clinical utility in spinal fusion and fracture repair. Yet its therapeutic translation is hindered by its paradoxical biology. Beyond regeneration, BMP2 provokes inflammatory signaling, upregulating cytokines like IL-6 and TNF-α, while driving catabolic enzymes (MMPs, ADAMTS) that degrade cartilage and intensify synovial inflammation, hallmarks of osteoarthritis (OA) progression. To address these limitations, current strategies emphasize fine-tuned regulation of BMP2 activity rather than broad stimulation. Emerging approaches include endogenous antagonists (Noggin, Gremlin), receptor decoys, selective BMPR1 blockade, spatiotemporally controlled delivery systems, and combinatorial use with stem cell or anti-inflammatory therapies. Such precision-based modulation aims to preserve BMP2's regenerative properties while suppressing its pathological consequences. Therefore, a deeper understanding of BMP2 signaling dynamics in joint biology is essential for unlocking safe therapeutic potential in OA management.

DNA N6-methyladenine (6 mA) has recently been recognized as a novel epigenetic modification, with ALKBH4 identified as a specific demethylase. However, the role of ALKBH4 and DNA 6 mA in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL) remains unclear. Tissue samples from OPLL patients and normal posterior longitudinal ligaments were collected, and ligament fibroblastic cells (LFCs) were isolated from OPLL tissues using primary culture. The expression and functional relevance of ALKBH4 in OPLL were investigated through reverse transcription quantitative polymerase chain reaction and western blot analyses. Osteogenic potential was further assessed using alizarin red S staining and alkaline phosphatase activity assays. Methylation status was evaluated by enzyme-linked immunosorbent assay and chromatin immunoprecipitation. Furthermore, the regulatory role of ALKBH4 in LFC ossification was investigated through the bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin pathways. ALKBH4 expression was significantly elevated in both OPLL tissues and LFCs, whereas global 6 mA levels and BMP2-associated 6 mA were reduced. Overexpression of ALKBH4 promoted the ossification of LFCs, while its knockdown suppressed osteogenesis. ALKBH4-mediated DNA demethylation at the 6 mA site facilitated Yin Yang 1 (YY1) binding to the BMP2 promoter, enhancing BMP2 transcription and driving ossification. Silencing of BMP2, Wnt/β-catenin, or YY1 attenuated the pro-ossification effects of ALKBH4. Furthermore, the mutation that affects the action of ALKBH4 at the 6 mA site fails to induce the osteogenic effect of LFC. These findings demonstrate that ALKBH4 regulates OPLL progression by modulating BMP2 and Wnt/β-catenin signaling and by promoting BMP2 transcription through site-specific demethylation in human OPLL tissues and primary LFCs. ALKBH4 may therefore represent a promising therapeutic target for the management of OPLL.

Drosophila male germline stem cells (GSCs) reside at the testis tip, surrounding a cluster of niche cells known as the hub. Bone Morphogenetic Protein (BMP) ligands secreted from the hub exert both contact-dependent and -independent effects. In close proximity to the niche, BMP signaling maintains stem cells by suppressing transcription of the key differentiation factor Bag of Marbles (Bam). In contrast, the diffusible fraction of BMP promotes differentiation of cells by activating bam expression. How a single signaling pathway produces such opposing outcomes has remained unclear. Here, we show that the diffusible BMP fraction induces bam transcription by repressing the transcriptional repressor Brinker (Brk). We further found that brk mRNA and protein display a highly heterogeneous distribution pattern within interconnected spermatogonia, suggesting that Brk has a distinct role in a subset of transit-amplifying cells. Taken together, our findings suggest a mechanism whereby a single niche-derived factor modulates reciprocal outcomes inside versus outside the niche, which is essential for tissue homeostasis. Given the widespread role of BMP signaling across stem cell niches, this mechanism might represent a general strategy for balancing stem cell self-renewal and differentiation.

Enhancing retinal photoreceptor neurite outgrowth with small molecules and growth factors.

Functionalized osteogenic extracellular vesicles derived from BMP9-stimulated mesenchymal stem cells (MSCs) effectively induce bone regeneration.

Bone morphogenetic protein-2 (BMP-2) regulates cell differentiation and proliferation. However, its role in colorectal cancer (CRC) remains debatable owing to potential oncogenic effects. Here, we investigated the role of BMP-2 in modulating CRC progression, particularly in regulating the Hippo signaling pathway. Exposure to recombinant human BMP-2 (rhBMP-2) resulted in a concentration-dependent decrease in CRC cell proliferation, leading to G1 cell cycle arrest. This effect was associated with the increased expression of p53, p21, and Smad4, while the levels of cyclin D1, cyclin-dependent kinase 4 (CDK4), and CDK6 decreased. Additionally, rhBMP-2 promoted apoptosis by decreasing poly (ADP-ribose) polymerase and caspase-9 expression while increasing their cleaved forms. It also activated the Hippo signaling cascade, enhancing the expression of mammalian sterile 20-like kinase 1/2, Mps One Binder 1 (MOB1), phosphorylated MOB1, and Salvador homolog, along with elevated levels of phosphorylated yes-associated protein (YAP), while concurrently suppressing total YAP expression. This resulted in cytoplasmic sequestration and subsequent degradation of YAP, thereby attenuating the transcription of YAP-responsive genes such as Connective Tissue Growth Factor. Silencing of Ras association domain family member 1 restored the rhBMP-2-induced decrease in cell viability, whereas silencing YAP further reduced the viability of CRC cell lines. Administering rhBMP-2 significantly suppressed tumor expansion in a mouse model of CRC, further supporting its potential as an antitumor agent. Collectively, these results indicate that rhBMP-2 mitigates CRC progression by activating the Hippo signaling pathway and suppressing YAP-mediated oncogenic processes, thereby highlighting its potential as a therapeutic agent that warrants further clinical evaluation.

Gastrointestinal cancer (GIC) frequently causes cancer cachexia, the major feature of which is the loss of skeletal muscle mass. The degradation of muscular proteins by cancer‑derived factors in the major pathogenesis of cancer‑induced muscle wasting is a known phenomenon. However, this mechanism has mainly been demonstrated using rodent cancer cells, and it may not always be applicable to human cancer types. Impaired skeletal muscle differentiation and regeneration have attracted attention as alternative inducers of cancer cachexia. The present study revealed that conditioned medium from four human GIC cell lines inhibited C2C12 myoblast differentiation by inducing the expression of the inhibitor of DNA binding (Id) proteins Id1 and Id3, which mediated via bone morphogenetic protein (BMP)‑Smad signaling. The results suggested that BMP‑Smad1/5/8‑Id signaling inhibited the expression of a MRF member, myogenin and its downstream myogenic genes, thus leading to unsuccessful differentiation into myotubes. Furthermore, the present study identified high levels of BMP4 secretion from these four human GIC cell lines and demonstrated that an inhibitor of BMP receptor, dorsomorphin or abrogation of BMP4 by siRNA in the GIC cells restored myogenic differentiation in C2C12 cells. The present study uncovered, for the first time, that BMP4 derived from human GIC cells exogenously inhibited myoblast differentiation by activating the Smad1/5/8‑Id signaling axis. In the future, this in vitro study may help to elucidate the complicated mechanisms underlying cancer‑induced cachexia in humans.

Targeting NBL1/PI3K/AKT axis to enhance the chemosensitivity and radiosensitivity of esophageal squamous cell carcinoma.

Sustained release PLGA microspheres loaded with a bone-affinity Bmp2 enhance fracture healing and mitigate heterotopic ossification.

Sensory innervation of developing organs is influenced by molecular cues secreted from surrounding tissues, yet the mechanisms coordinating this tissue-tissue communication are not well understood. Tooth innervation during root development provides a valuable model to investigate how local mesenchymal cues regulate axonal growth under physiological conditions, as innervation begins and progresses alongside tooth root formation. Here we identify the histone demethylase KDM6B, expressed in cranial neural crest-derived dental mesenchyme, as a critical extrinsic regulator of tooth sensory innervation. Loss of Kdm6b in dental mesenchyme severely impairs trigeminal axon entry and branching into the dental pulp, leading to tooth root development defects. Mechanistically, loss of Kdm6b reduces the expression of bone morphogenetic protein (BMP) pathway antagonist Bambi in the dental mesenchyme by modulating H3K27me3 chromatin marks, causing overactivation of BMP signaling, which then directly suppresses the expression of nerve growth factor (Ngf). Compromised NGF activity thereby diminishes mesenchymal support for sensory axon extension during tooth root development. Haploinsufficiency of Ezh2, which antagonizes Kdm6b, or Bmpr1a, a key BMP receptor, partially rescues Ngf expression, sensory innervation, and tooth root development defects in Kdm6b mutants. Together, these findings reveal that epigenetic regulation within mesenchymal cells governs sensory innervation during organogenesis, uncovering important regulatory mechanisms that may inform future strategies for restoring innervation in tissue regenerative approaches.

Acute liver failure (ALF) is characterized by extensive hepatocyte necrosis and limited treatment options. Adipose-derived stem cells (ADSCs) show potential for liver regeneration, yet the mechanisms regulating their hepatic differentiation remain unclear. Human ADSCs were infected with lentiviruses to overexpress or silence miR-204-5p, Murine double minute 2 (MDM2), E2F transcription factor 8 (E2F8), or bone morphogenetic protein 4 (BMP4). qPCR, immunofluorescence, and western blot detected mRNA and protein levels of hepatic markers-including hepatocyte nuclear factor 4 alpha (HNF4α), albumin (ALB), and alpha-fetoprotein (AFP). Periodic acid-Schiff (PAS) staining assessed glycogen storage, while enzyme-linked immunosorbent assay (ELISA) measured ALB and urea secretion. Dual-luciferase reporter and co-immunoprecipitation (Co-IP) assays verified molecular interactions and ubiquitination. A Carbon Tetrachloride (CCl₄)-induced ALF model in mice was adopted to investigate the therapeutic potential of miR-204-5p-overexpression ADSCs by fluorescence imaging, histology, tunel staining, and measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Invitro, miR-204-5p suppresses MDM2 expression, thereby reducing MDM2-mediated ubiquitination and degradation of E2F8. Stabilized E2F8 transcriptionally activates BMP4, ultimately promoting the hepatogenic differentiation of ADSCs, as evidenced by increased ALB and HNF4α expression, enhanced glycogen synthesis, and elevated urea production. In a CCl₄-induced ALF mouse model, miR-204-5p-modified ADSCs localized to the liver, reduced necrosis and apoptosis, improved hepatic architecture, and decreased ALT and AST levels. miR-204-5p promotes hepatogenic differentiation of ADSCs and ameliorates acute liver failure through the MDM2/E2F8/BMP4 signaling axis, providing a potential molecular target to enhance stem cell-based liver regeneration therapy.

TUSC3 serves as a rate-limiting gatekeeper of a glycan-mediated ER triage checkpoint for BMP4/Dpp.

Retrospective clinical study. Investigating the fusion effect and side effect profile between low-dose E.BMP-2 and mammalian rhBMP-2. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used in anterior and lateral lumbar spinal fusion surgery to stimulate fusion. This study aims to evaluate the clinical and radiologic outcomes of 2 commercially available preparations of rhBMP-2, Chinese hamster ovarian cell-derived rhBMP-2 (CHO-rhBMP-2) and Escherichia coli-derived rhBMP2 (E.BMP-2). Two groups of patients who underwent minimally invasive lumbar spinal interbody fusion surgery (between L1 and S1) with E.BMP2 and CHO-derived rhBMP-2 from 2018 to 2024 were included. Preoperative and postoperative clinical outcome scores and radiologic parameters were compared. Interval radiographs were done to assess fusion and complication rates. A total of 75 patients and 154 levels were involved. There was no significant difference in baseline characteristics between the 2 groups. The average dosage of rhBMP-2 was 0.50mg per level in the E.BMP-2 group and 1.91mg per level in the rhBMP-2 group. There was no significant difference in postoperative clinical outcome scores and segmental lordosis. Fusion rates on dynamic radiographs were 100% for both groups. Fusion rate on CT scan was 86.4% (n=19) in the E.BMP-2 group, whereas it was 78.3% (n=18) in the rhBMP-2 group. One patient from each group underwent revision surgery for symptomatic cage subsidence. This study demonstrates that low-dose E.BMP-2 use in lumbar spinal fusion surgery is not inferior to a traditionally available rhBMP-2. Comparable fusion rate with lower dose of bone graft further highlights its efficacy. Low-dose E.BMP-2 is thus a safe alternative osteo-inductive agent that can facilitate spinal fusion.

This review provides an overview of adipose tissue plasticity and adipogenesis as central processes regulating adipose tissue expansion, remodeling, and metabolic function in health and obesity, highlighting their relevance as potential therapeutic targets. Adipogenesis is a tightly regulated process involving the differentiation of adipose progenitor cells into mature adipocytes through coordinated transcriptional cascades, primarily driven by peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding protein (C/EBP) family members. This process is further modulated by multiple signaling pathways, including wingless-related integration site (Wnt), bone morphogenetic proteins (BMPs), and insulin signaling, which collectively regulate adipocyte differentiation and metabolic function. Under physiological conditions, the adipose tissue exhibits remarkable plasticity, with adipogenesis supporting lipid buffering capacity and tissue renewal. In obesity, however, chronic nutrient excess and hormonal dysregulation impair this process, favoring adipocyte hypertrophy, hypoxia, and chronic inflammation. These alterations disrupt adipokine secretion and promote ectopic lipid deposition, thereby contributing to metabolic disorders, including insulin resistance and cardiometabolic disease. Adipose tissue plasticity and adipogenesis are critical determinants of metabolic health. Dysregulation of these processes underlies adipose tissue dysfunction and contributes to the development of obesity-related comorbidities. Targeting adipogenesis and promoting healthy adipose tissue remodeling represent promising strategies for restoring metabolic homeostasis and mitigating obesity-associated diseases.

Irregular-shaped bone defects are commonly encountered in clinical practice, and various biomaterials have been developed to address these issues. Injectable in situ forming hydrogels not only effectively fill irregular-shaped defects but also provide a suitable growth environment for host cells. In this study, we developed an injectable nanocomposite hydrogel, which includes chitosan oligosaccharides (COS), DL-α-Glycerol phosphate magnesium salt hydrate (Mg-GP), 4-arm PEG-Succinimidyl Carbonate (4-arm-PEG-SC), and mesoporous polydopamine (MPDA) nanoparticles loaded with bone morphogenetic protein-2 (BMP-2). The injectable hydrogel demonstrates excellent physical properties, including injectability, self-healing, photothermal property, appropriate swelling (182%) and degradation rates (59%), sufficient mechanical strength (280kPa) and adhesion (10kPa). Additionally, the injectable hydrogel exhibits multiple biological effects, including controlled release of BMP-2 (59.1%) and magnesium ions (55.1%), antioxidant and antibacterial properties, promotion of cell proliferation and migration, regulation of immune microenvironment, and stimulation of osteogenesis and angiogenesis. In summary, both in vitro and in vivo experiments demonstrate that the injectable nanocomposite hydrogel may represent a promising minimally invasive solution for endogenous bone regeneration.

Pathogenesis of proliferative enteropathy caused by Lawsoniaintracellularis.

A systemic role of macrophage-derived BMP2/4 homolog Dpp in inhibiting sterol hormone synthesis under dietary stress.

Objective: To establish and identify a culture system for skin organoids based on human induced pluripotent stem cells (hiPSCs). Methods: This study was a basic research with a self-controlled pre-post design. Human primary skin fibroblasts (Fbs) were obtained from discarded hair follicle tissue of a 45-year-old male patient undergoing hair transplant surgery at Tongji Medical College of Huazhong University of Science and Technology. Primary skin Fbs were induced into hiPSCs, which were then cultured to form three-dimensional aggregates. Then the induced differentiation was performed as followings. On differentiation day 0 (the day of differentiation initiation), the three-dimensional aggregates were transferred to ultra-low attachment culture plate and cultured in E6 medium supplemented with Matrigel, transforming growth factor-β type Ⅰ receptor inhibitor of SB431542, basic fibroblast growth factor (bFGF), and bone morphogenetic protein-4 to induce non-neural ectoderm formation. On differentiation day 3, one-quarter volume of E6 medium supplemented with bone morphogenetic protein signaling pathway inhibitor of LDN193189 and bFGF was added to the original medium to continue culturing and to induce the formation of cranial neural crest cells. On differentiation day 6, culture continued with approximately 3/5 volume of plain E6 medium added to the original medium. Half-medium changes were performed on differentiation days 8 and 10 (once each), followed by continued culture. On differentiation day 12, cell clumps were seeded into new ultra-low attachment culture plate to continue culturing, and epidermal self-assembly was induced using organoid maturation medium supplemented with Matrigel. On differentiation day 15, a half-medium change was performed, and culture was continued. On differentiation day 18, the original medium was replaced with organoid maturation medium supplemented with α-melanocyte-stimulating hormone to continue culturing. Starting from differentiation day 21, half-medium changes were performed every 3 days, and culture continued. After differentiation initiation, the stage-specific morphological characteristics of hiPSC differentiation into skin organoids were observed daily. Immunofluorescence staining was performed to assess skin organoids on different days of differentiation: on day 12 for the presence of mesenchymal cells, on day 20 for epidermal terminal differentiation, on day 35 for mesenchymal and epithelial structure formation as well as hair follicle stem cell and basal layer keratinocyte related characteristics, on day 55 for dermal papilla formation, on day 75 for hair germ-like structure formation, and on day 90 for organoid proliferative activity. Fluorescence probe staining was performed on differentiation day 110 to detect hair follicle formation, as well as lipid deposition and sebaceous gland-like structure formation. Results: On differentiation day 0, hiPSCs formed three-dimensional aggregates with clear boundaries and relatively uniform size. On differentiation day 3, ectoderm-like structures appeared on the surface of the aggregates, accompanied by non-epithelial-like cells beginning to migrate outward. During differentiation days 6 to 8, mesenchymal cells and neuroglial-like cells gradually increased. During differentiation days 12 to 18, organoids with spatial heterogeneity gradually formed within the aggregates, exhibiting preliminary epidermal-dermal-like bilayer structures. On differentiation day 60, hair germ-like structures were observed. During differentiation days 80 to 130, more mature hair germ-like structures and hair follicle-like structures gradually emerged. Immunofluorescence detection showed that on differentiation day 12, early mesenchymal cells were observed around the skin organoids. On differentiation day 20, keratinocytes emerged in the outer layer of the skin organoids. On differentiation day 35, dermal-like cells emerged in the skin organoids, forming distinct spatial compartments with epithelial-like structures, accompanied by the presence of basal layer-like cell populations. On differentiation day 55, dermal papilla-like cell populations were detected and were spatially adjacent to epidermal regions. On differentiation day 75, thickened epithelial-like structures growing inward were observed in localized areas of the skin organoids, along with cell aggregation forming hair germ-like structures; dermal papilla-like cell populations were detected in regions adjacent to the hair germ and were spatially adjacent to epithelial structures. On differentiation day 90, proliferating cell enrichment was observed in the hair germ region. Fluorescence probe staining showed that by differentiation day 110, more mature hair follicle-like structures, hair shaft-like protrusions, lipid deposition, and sebaceous gland-like structures were observed in the skin organoids. Conclusions: By stage-wise modulation of key signaling pathways, we successfully established a hiPSC-based a culture system for skin organoids. The induced differentiation process of this system highly mimics the in vivo developmental program of skin and hair follicles, resulting in the reconstitution of a complex in vitro skin model with hair follicle-like structures.

BackgroundThis study compares clinical and radiographic outcomes in alveolar bone grafting (ABG) using iliac crest bone graft (ICBG) alone, demineralized bone matrix (DBM) with recombinant human bone morphogenetic protein-2 (rhBMP-2), and ICBG with recombinant human bone morphogenetic protein-2 with demineralized bone matrix (rhBMP2/DBM).PurposeWe evaluated differences in clinical success and radiographic bone formation among grafting techniques for secondary alveolar cleft repair.Study Design, Setting, and SampleRetrospective cohort study of patients undergoing secondary ABG for cleft alveolus between 2017 and 2023 at a tertiary children's hospital.Independent VariableType of grafting technique: ICBG alone, DBM with rhBMP-2, or ICBG with rhBMP-2.Main Outcome VariablesThe primary outcome was radiographic success (bony bridging on cone-beam computed tomography). Secondary outcomes included vertical bone height and reoperation.CovariatesAge, sex, cleft laterality, and graft type.AnalysesDescriptive statistics and comparative analyses were performed. Statistical significance was set at P < .05.ResultsA total of 432 patients (527 clefts) were included: 196 ICBG, 284 DBM + rhBMP-2, and 47 ICBG + rhBMP-2. Radiographic success was highest in the ICBG + rhBMP-2 group (89.4%) compared with ICBG (65.3%; P = .001) and DBM + rhBMP-2 (61.6%; P < .001). Mean vertical bone height was greater in the ICBG + rhBMP-2 group (7.4 ± 2.6 mm) versus ICBG (4.7 ± 1.9 mm; P < .001) and DBM + rhBMP-2 (4.4 ± 1.2 mm; P < .001).Conclusions and RelevanceICBG combined with rhBMP-2 demonstrates improved radiographic bone formation and vertical height compared with alternative grafting strategies, without increasing reoperation rates.