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Introduction Osteoarthritis is a highly prevalent, age-associated joint disease characterized by cartilage degeneration, joint dysfunction, and chronic pain. We previously developed a bone morphogenetic protein 7 derived peptide p[63–82], which may be a novel disease-modifying treatment option for OA. In this study we aimed to optimize the bioactivity and biostability of this peptide in the intra-articular environment to evaluate the therapeutic potential of these peptides to treat osteoarthritis. Methods 33 peptide modifications of p[63–82] were custom-designed and synthesized to optimize the bioactivity. Chondrocytes and synovial fluid were collected from end-stage osteoarthritic patients at total knee arthroplasty surgery. To validate improvements in bioactivity, gene expression analysis, glycosaminoglycan content, matrix metalloproteinase-13 protein levels and alkaline phosphatase activity was measured. Results Several biochemical approaches were used to explore optimization of the original p[63–82] peptide. One cyclized peptide (C2) was able to significantly increase the expression of collagen type 2 and decrease expression of collagen type 10 , matrix metalloproteinase-13 and prostaglandin-endoperoxide synthase 2 . The linear p[63–82] peptide and the cyclic peptide variant C2 in the same concentration were effective in suppressing the osteoartritic phenotype in SW1353 cells, despite the presence of interleukin-1β or osteoarthritic-synovial fluid. However, peptide variant C2 had a significantly more favorable bioactivity as compared to p[63–82] in reducing matrix metalloproteinase-13 protein levels in the osteoarthritic-synovial fluid exposed condition. At lower concentrations, the cyclic peptide C2 showed a higher bioactivity as compared to the linear p[63–82] peptide. When the activity of both peptides on primary human articular chondrocytes was evaluated, we found that the linear p[63–82] peptide as well as peptide C2 counteract the hypertrophic and inflammatory state of primary OA chondrocytes. Conclusion This study demonstrates that among various tested modifications of p[63–82], one cyclic variant (C2) showed similar results in bioactivity as compared to the linear peptide p[63–82], whilst the other modified peptide variants had inactive bioactive properties as compared to the original p[63–82] peptide. This highlights the challenge in enhancing peptide properties without compromising their biological activity and emphasises the need for a cautious approach in peptide modification for therapeutic use. This research underscores that while cyclization and other structural changes may offer benefits, they should be carefully evaluated on a case-by-case basis.

Background Accumulating evidence indicates that intervertebral disc degeneration (IDD) is associated with diabetes mellitus (DM), while the underlying mechanisms still remain elusive. Herein, the current study sought to explore the potential molecular mechanism of IDD in diabetic rats based on transcriptome sequencing data. Methods Streptozotocin (STZ)-induced diabetes mellitus type 1 (T1DM) rats were used to obtain the nucleus pulposus tissues for transcriptome sequencing. Next, differentially expressed genes (DEGs) in transcriptome sequencing data and GSE34000 microarray dataset were obtained and intersected to acquire the candidate genes. Moreover, GO and KEGG enrichment analyses were performed to analyze the cellular functions and molecular signaling pathways primarily regulated by candidate DEGs. Results A total of 35 key genes involved in IDD of T1DM rats were mainly enriched in the extracellular matrix (ECM) and cytokine adhesion binding-related pathways. NLRP3 inflammasome activation promoted the pyroptosis of nucleus pulposus cells (NPCs). Besides, BMP7 could affect the IDD of T1DM rats by regulating the inflammatory responses. Additionally, NPCs were isolated from STZ-induced T1DM rats to illustrate the effects of BMP7 on IDD of T1DM rats using the ectopic expression method. Both in vitro and in vivo experiments validated that BMP7 alleviated IDD of T1DM rats by inhibiting NLRP3 inflammasome activation and pyroptosis of NPCs. Conclusion Collectively, our findings provided novel mechanistic insights for understanding of the role of BMP7 in IDD of T1DM, and further highlighted BMP7 as a potential therapeutic target for preventing IDD in T1DM.

BackgroundBMP7 has been shown to have neuroprotective effects and to alleviate demyelination. However, its role in trigeminal neuralgia (TN) has not been well investigated. The current study aims to determine whether BMP7 plays a role in demyelination, its effects on pain behaviors and mechanism of action in rats with TN.MethodsWe used an infraorbital-nerve chronic-constriction injury (ION-CCI) to establish a rat model of TN. Adeno-associated viruses (AAVs) were injected into the rats to upregulate or downregulate BMP7. The mechanical withdrawal thresholds (MWT) of the injured rats were detected using Von Frey filaments. The changes in expression levels of BMP7 and oligodendrocyte (OL) markers were examined by western blotting, quantitative real-time PCR, immunofluorescence, and transmission electron microscopy.ResultsThe ION-CCI induced mechanical allodynia, demyelination, and loss of OLs with a reduction of BMP7. Short-hairpin RNA (shRNA)-BMP7 that inhibited BMP7 expression also caused mechanical allodynia, demyelination, and loss of OLs, and its mechanism may be OL apoptosis. Overexpressing BMP7 in the trigeminal spinal subnucleus caudalis(VC) with AAV-BMP7 relieved all three phenotypes induced by the CCI, and its mechanism may be alleviating OLs apoptosis. Two signal pathways associated with apoptosis, STAT3 and p65, were significantly downregulated in the VC after CCI and rescued by BMP7 overexpression.ConclusionBMP7 can alleviate TN by reducing OLs apoptosis and subsequent demyelination. The mechanism behind this protection could be BMP7-mediated activation of the STAT3 and NF-κB/p65 signaling pathway and subsequent decrease in OL apoptosis. Importantly, our study presents clear evidence in support of BMP7 as a possible therapeutic target for the treatment of TN.

Chemotherapy drugs efficiently eradicate rapidly dividing differentiated cells by inducing cell death, but poorly target slowly dividing cells, including cancer stem cells and dormant cancer cells, in the later course of treatment. Prolonged exposure to chemotherapy results in a decrease in the proportion of apoptotic cells in the tumour mass. To investigate and characterize the molecular basis of this phenomenon, microarray-based expression analysis was performed to compare tHcred 2 -DEVD-EGFP-caspase 3-sensor transfected C-26 tumour cells that were harvested after engraftment into mice treated with or without 5-FU. Peritoneal metastasis was induced by intraperitoneal injection of C-26 cells, which were subsequently reisolated from omental metastatic tumours after the mice were sacrificed by the end of the 10th day after tumour injection. The purity of reisolated tHcred2-DEVD-EGFP-caspase 3-sensor-expressing C-26 cells was confirmed using FLIM, and total RNA was extracted for gene expression profiling. The validation of relative transcript levels was carried out via real-time semiquantitative RT‒PCR assays. Our results demonstrated that chemotherapy induced the differential expression of mediators of cancer cell dormancy and cell survival-related genes and downregulation of both intrinsic and extrinsic apoptotic signalling pathways. Despite the fact that some differentially expressed genes, such as BMP7 and Prss11, have not been thoroughly studied in the context of chemoresistance thus far, they might be potential candidates for future studies on overcoming drug resistance.

Abstract Context The role of immune-related genes (IRGs) in thyroid cancer dedifferentiation and accompanying immune exhaustion remains largely unexplored. Objective To construct a significant IRG-based signature indicative of dedifferentiation and immune exhaustion in thyroid cancer. Design and Settings One exploratory cohort and 2 validation cohorts were used to identify stably dysregulated IRGs in dedifferentiated thyroid cancer (DDTC) and to obtain independent risk factors for dedifferentiation. The IRGs formed a gene signature, whose predictive value was tested by the receiver operating characteristic curve. Correlations between the signature and differentiation-related genes, immune checkpoints, and prognosis were analyzed. Gene set enrichment analyses were performed to identify related signaling pathways. Results Four IRGs (PRKCQ, PLAUR, PSMD2, and BMP7) were found to be repeatedly dysregulated in DDTC, and they formed an IRG-based signature with a satisfactory predictive value for thyroid cancer dedifferentiation. Correlation analyses revealed that immune checkpoints were closely related to the 4 IRGs and the IRG-based signature, which was significantly associated with the histological subtype (P = 0.026), lymph node metastasis (P = 0.001), and BRAFV600E mutation (P < 0.001). The downregulated expression of PRKCQ shortened the disease-free survival for patients with thyroid cancer. Furthermore, we identified several signaling pathways inherently associated with the IRG-based signature. Conclusions This study suggests that IRGs participate in the dedifferentiation and immune exhaustion process of thyroid cancer and are potential biomarkers for DDTC.

Carnivora is a successful taxon in terms of dietary diversity. We investigated the dietary adaptations of carnivoran dentition and the developmental background of their dental diversity, which may have contributed to the success of the lineage. A developmental model was tested and extended to explain the unique variability and exceptional phenotypes observed in carnivoran dentition. Carnivorous mammalian orders exhibited two distinct patterns of dietary adaptation in molars and only Carnivora evolved novel variability, exhibiting a high correlation between relative molar size and the shape of the first molar. Studies of Bmp7-hetero-deficient mice, which may exhibit lower Bmp7 expression, suggested that Bmp7 has pleiotropic effects on these two dental traits. Its effects are consistent with the pattern of dietary adaptation observed in Carnivora, but not that observed in other carnivorous mammals. A molecular evolutionary analysis revealed that Bmp7 sequence evolved by natural selection during ursid evolution, suggesting that it plays an evolutionary role in the variation of carnivoran dentition. Using mouse experiments and a molecular evolutionary analysis, we extrapolated the causal mechanism of the hitherto enigmatic ursid dentition (larger M2 than M1 and M3). Our results demonstrate how carnivorans acquired novel dental variability that benefits their dietary divergence.

Bone tissue engineering (BTE) is a promising alternative to autologous bone grafting for the clinical treatment of bone defects, and inorganic/organic composite hydrogels as BTE scaffolds are a hot spot in current research. The construction of nano-hydroxyapatite/gelatin methacrylate/oxidized sodium alginate (nHAP/GelMA/OSA), abbreviated as HGO, composite hydrogels loaded with bone morphogenetic protein 7 (BMP7) will provide a suitable 3D microenvironment to promote cell aggregation, proliferation, and differentiation, thus facilitating bone repair and regeneration. Dually-crosslinked hydrogels were fabricated by combining GelMA and OSA, while HGO hydrogels were formulated by incorporating varying amounts of nHAP. The hydrogels were physically and chemically characterized followed by the assessment of their biocompatibility. BMP7-HGO (BHGO) hydrogels were fabricated by incorporating suitable concentrations of BMP7 into HGO hydrogels. The osteogenic potential of BHGO hydrogels was then validated through in vitro experiments and using rat femoral defect models. The addition of nHAP significantly improved the physical properties of the hydrogel, and the composite hydrogel with 10% nHAP demonstrated the best overall performance among all groups. The selected concentration of HGO hydrogel served as a carrier for BMP7 loading and was evaluated for its osteogenic potential both in vivo and in vitro. The BHGO hydrogel demonstrated superior in vitro osteogenic induction and in vivo potential for repairing bone tissue compared to the outcomes observed in the blank control, BMP7, and HGO groups. Using hydrogel containing 10% HGO appears promising for bone tissue engineering scaffolds, especially when loaded with BMP7 to boost its osteogenic potential. However, further investigation is needed to optimize the GelMA, OSA, and nHAP ratios, along with the BMP7 concentration, to maximize the osteogenic potential.

Excessive activation of pro-inflammatory (M1) microglia phenotypes after spinal cord injury (SCI) disrupts tissue repair and increases the risk of secondary SCI. We previously reported that adeno-associated virus (AAV) mediated delivery of bone morphogenetic protein 7 (BMP7) promotes functional recovery after SCI by reducing oligodendrocyte loss and demyelination; however, little is known about the early effects of BMP7 in ameliorating neuroinflammation in the acute SCI phase. Herein, we demonstrate that treatment with recombinant human BMP7 (rhBMP7) suppresses the viability of LPS-induced HMC3 microglia cells and increases the proportion with the M2 phenotype. Consistently, in a rat SCI model, rhBMP7 decreases the activation of microglia and promotes M2 polarization. After rhBMP7 administration, the STAT3 signaling pathway was activated in LPS-induced HMC3 cells and microglia in spinal cord lesions. Furthermore, the levels of TNF-α and IL-1β were significantly decreased in cell culture supernatants, lesion sites of injured spinal cords, and cerebrospinal fluid circulation after rhBMP7 administration, thus reducing neuron loss in the injured spinal cord and promoting functional recovery after SCI. These results provide insight into the immediate early mechanisms by which BMP7 may ameliorate the inflammation response to secondary SCI.

Mammalian cardiomyocytes (CMs) undergo maturation during postnatal heart development to meet the increased demands of growth. Here, we found that omentin-1, an adipokine, facilitates CM cell cycle arrest and metabolic maturation. Deletion of omentin-1 causes mouse heart enlargement and dysfunction in adulthood and CM maturation retardation in juveniles, including delayed cell cycle arrest and reduced fatty acid oxidation. Through RNA sequencing, molecular docking analysis, and proximity ligation assays, we found that omentin-1 regulates CM maturation by interacting directly with bone morphogenetic protein 7 (BMP7). Omentin-1 prevents BMP7 from binding to activin type II receptor B (ActRIIB), subsequently decreasing the downstream pathways mothers against DPP homolog 1 (SMAD1)/Yes-associated protein (YAP) and p38 mitogen-activated protein kinase (p38 MAPK). In addition, omentin-1 is required and sufficient for the maturation of human embryonic stem cell-derived CMs. Together, our findings reveal that omentin-1 is a pro-maturation factor for CMs that is essential for postnatal heart development and cardiac function maintenance.

The aim of the present study was to investigate the expression of bone morphogenetic protein 7 (BMP7) in cervical cancer tissues, the effect of BMP7 on the proliferation, migration and epithelial-mesenchymal transition (EMT) of cervical cancer HeLa cells and the possible mechanism involved. Immunohistochemistry was used to stain the cervical cancer tissues and benign or precancerous lesions. Lentivirus containing BMP7 knockdown was transfected in HeLa cells and western blotting was performed to analyze BMP7 expression. At the same time, the influence of BMP7 knockdown on the expression of phosphorylated (p)-mothers against decapentaplegic homolog 1/5/9 and EMT-related markers [epithelial-cadherin, neural-cadherin, Vimentin, Snail and Slug] was detected. Cell Counting Kit-8 was used to detect cell proliferation. Transwell migration and invasion assays were performed to measure cell invasion and migration. The cell cycle was detected by flow cytometry. Compared with normal cervical epithelial and paracancerous cells, the positive rate of BMP7 expression in cervical cancer tissues was significantly increased. As compared with the control group, the expression of BMP7 was decreased in HeLa cells transfected with lentivirus. The knockdown of BMP7 in cervical cancer HeLa cells inhibited cell proliferation, migration and invasion, resulted in G1 cell cycle arrest and reversed the EMT process. In addition, the expression of p-Smad1/5/9 was significantly decreased in HeLa cells with BMP7 knockdown. BMP7 is expected to be a possible target for the treatment of cervical cancer.