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Keloid is a typical fibrotic and inflammatory skin disease with unclear mechanisms and few therapeutic targets. In this study, we found that BMP1 was significantly increased in a collagen high-expressing subtype of fibroblast by reanalyzing a public single-cell RNA-sequence data set of keloid. The number of BMP1-positive fibroblast cells was increased in keloid fibrotic loci. Increased levels of BMP1 were further validated in the skin tissues and fibroblasts from keloid patients. Additionally, a positive correlation between BMP1 and the Keloid Area and Severity Index was found in keloid patients. In vitro analysis revealed collagen production, the phosphorylation levels of p65, and the IL-1ß secretion decreased in BMP1 interfered keloid fibroblasts. Besides, the knockdown of BMP1 inhibited the growth and migration of keloid fibroblast cells. Mechanistically, BMP1 inhibition downregulated the noncanonical TGF-ß pathways, including p-p38 and p-ERK1/2 signaling. Furthermore, we found the delivery of BMP1 siRNAs could significantly alleviate keloid in human keloid-bearing nude mice. Collectively, our results indicated that BMP1 exhibited various pathogenic effects on keloids as promoting cell proliferation, migration, inflammation, and ECM deposition of fibroblast cells by regulating the noncanonical TGF-ß/p38 MAPK, and TGF-ß/ERK pathways. BMP1-lowing strategies may appear as a potential new therapeutic target for keloid.
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Proteína Morfogenética Óssea 1 , Fibroblastos , Inflamação , Queloide , Queloide/metabolismo , Queloide/patologia , Queloide/genética , Humanos , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteína Morfogenética Óssea 1/metabolismo , Proteína Morfogenética Óssea 1/genética , Animais , Camundongos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , Masculino , Camundongos Nus , Proliferação de Células , Feminino , Movimento Celular , Fibrose , Adulto , Fator de Crescimento Transformador beta/metabolismo , Sistema de Sinalização das MAP QuinasesRESUMO
BACKGROUND AND OBJECTIVE: The pathogenesis of coronal suture craniosynostosis is often attributed to the dysregulated cellular dynamics, particularly the excessive proliferation and abnormal osteogenic differentiation of suture cells. Despite its clinical significance, the molecular mechanims of this condition remain inadequately understood. This study is dedicated to exploring the influence of the Periostin/Bone Morphogenetic Protein 1 (BMP1) axis on the growth and osteogenic maturation of Suture Mesenchymal Stem Cells (SMSCs), which are pivotal in suture homeostasis. METHODS: Neonatal TWIST Basic Helix-Loop-Helix Transcription Factor 1 heterozygous (TWIST1+/-) mice, aged one day, were subjected to adenoviral vector-mediated Periostin upregulation. To modulate Periostin/BMP1 levels in SMSCs, we employed siRNA and pcDNA 3.1 vectors. Histological and molecular characterizations, including hematoxylin and eosin staining, Western blot, and immunohistochemistry were employed to study suture closure phenotypes and protein expression patterns. Cellular assays, encompassing colony formation, 5-ethynyl-2'deoxyuridine, and wound healing tests were conducted to analyze SMSC proliferation and migration. Osteogenic differentiation was quantified using Alkaline Phosphatase (ALP) and Alizarin Red S (ARS) staining, while protein markers of proliferation and differentiation were evaluated by Western blotting. The direct interaction between Periostin and BMP1 was validated through co-immunoprecipitation assays. RESULTS: In the TWIST1+/- model, an upregulation of Periostin coupled with a downregulation of BMP1 was observed. Augmenting Periostin expression mitigated craniosynostosis. In vitro, overexpression of Periostin or BMP1 knockdown suppressed SMSC proliferation, migration, and osteogenic differentiation. Periostin knockdown manifested an inverse biological impact. Notably, the suppressive influence of Periostin overexpression on SMSCs was effectively counteracted by upregulating BMP1. There was a direct interaction between Periostin and BMP1. CONCLUSION: These findings underscore the significance of the Periostin/BMP1 axis in regulating craniosynostosis and SMSC functions, providing new insights into the molecular mechanisms of craniosynostosis and potential targets for therapeutic intervention.
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Craniossinostoses , Células-Tronco Mesenquimais , Camundongos , Animais , Osteogênese/genética , Periostina , Proteína Morfogenética Óssea 1/metabolismo , Craniossinostoses/genética , Craniossinostoses/metabolismo , Diferenciação Celular/genética , Células-Tronco Mesenquimais/metabolismo , Modelos Animais de Doenças , Proliferação de Células/genética , Células CultivadasRESUMO
Enigma protein, encoded by the PDLIM7 gene, is overexpressed in thyroid cancer in a stage-dependent manner, suggesting a potential involvement in the initiation and progression of thyroid cancer. The Enigma interacts with several cellular pathways, including PI3K/AKT, MDM2, and BMP-1. The Enigma is regulated by microRNAs. Specifically, we showed that the Enigma protein upregulation corresponds to the downregulation of Let-7 family genes. There is limited research on the interactions and regulation of the Enigma with other proteins/genes in thyroid cancer tissues, indicating a gap in current knowledge. Our aim is to establish the Enigma as a biomarker. We also aim to study the interacting partners of the Enigma signaling pathways and their probable miRNA regulation in thyroid cancer progression. Using Western blotting, densitometric analysis, immunoprecipitation (IP), and reverse IP, we detected the protein expression and protein-protein interactions in the corresponding papillary thyroid carcinomas (PTCs). Utilizing real-time qPCR assay and Pearson's correlation test, we highlighted the correlation between PDLIM7 and Let-7g gene expression in the same tissues. The results showed the differential upregulations of the Enigma protein in different stages of PTCs compared to benign tissues along with AKT, VDR, BMP-1, and MDM2 proteins. Loss of DBP was observed in a subset of PTCs. Strong interactions of the Enigma with PI3K/AKT and MDM2 were noted, along with a weaker BMP-1 interaction. Pearson's correlation coefficient analysis between PDLIM7 and let-7g gene expression was significant (p < 0.05); however, there was a weak inverse correlation (r = -0.27). The study suggests the potential utility of the PDLIM7-qPCR assay as a biomarker for thyroid cancer. The Enigma's interactions with key signaling pathways may provide valuable insights into the development of thyroid cancer. The study contributes to understanding the molecular mechanisms involving the Enigma protein in thyroid cancer and highlights its potential as a biomarker.
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Proteínas com Domínio LIM , MicroRNAs , Neoplasias da Glândula Tireoide , Humanos , Biomarcadores , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Proteínas com Domínio LIM/genéticaRESUMO
BACKGROUND: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all adult malignancies. Clear cell renal cell carcinoma (ccRCC), which comprises 70-80% of all RCC cases, is the most common histological subtype. METHODS: ccRCC transcriptome data and clinical information were downloaded from the TCGA database. We used the TCGA and GEPIA databases to analyze relative expression of BMP1 in various types of human cancer. GEPIA was used to perform survival analysis for BMP1 in various cancer types. Upstream binding miRNAs of BMP1 were obtained through several important target gene prediction tools. StarBase was used to predict candidate miRNAs that may bind to BMP1 and candidate lncRNAs that may bind to hsa-miR-532-3p. We analyzed the association between expression of BMP1 and immune cell infiltration levels in ccRCC using the TIMER website. The relationship between BMP1 expression levels and immune checkpoint expression levels was also investigated. RESULTS: BMP1 was upregulated in GBM, HNSC, KIRC, KIRP and STAD and downregulated in KICH and PRAD. Combined with OS and DFS, BMP1 can be used as a biomarker for poor prognosis among patients with KIRC. Through expression analysis, survival analysis and correlation analysis, LINC00685, SLC16A1-AS1, PVT1, VPS9D1-AS1, SNHG15 and the CCDC18-AS1/hsa-miR-532-3p/BMP1 axis were established as the most potential upstream ncRNA-related pathways of BMP1 in ccRCC. Furthermore, we found that BMP1 levels correlated significantly positively with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. CONCLUSION: Our results demonstrate that ncRNA-mediated high expression of BMP1 is associated with poor prognosis and tumor immune infiltration in ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , MicroRNAs , RNA Longo não Codificante , Humanos , Proteína Morfogenética Óssea 1 , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Regulação para Cima/genéticaRESUMO
Transforming growth factor ß (TGFß) is required for long-term memory (LTM) for sensitization in Aplysia. When LTM is induced using a two-trial training protocol, TGFß inhibition only blocks LTM when administrated at the second, not the first trial. Here, we show that TGFß acts as a "repetition detector" during the induction of two-trial LTM. Secretion of the biologically inert TGFß proligand must coincide with its proteolytic activation by the Bone morphogenetic protein-1 (BMP-1/Tolloid) metalloprotease, which occurs specifically during trial two of our two-trial training paradigm. This paradigm establishes long-term synaptic facilitation (LTF), the cellular correlate of LTM. BMP-1 application paired with a single serotonin (5HT) pulse induced LTF, whereas neither a single 5HT pulse nor BMP-1 alone effectively did so. On the other hand, inhibition of endogenous BMP-1 activity blocked the induction of two-trial LTF. These results suggest a unique role for TGFß in the interaction of repeated trials: during learning, repeated stimuli engage separate steps of the TGFß cascade that together are necessary for the induction of long-lasting memories.
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Potenciação de Longa Duração , Fator de Crescimento Transformador beta , Animais , Potenciação de Longa Duração/fisiologia , Fator de Crescimento Transformador beta/farmacologia , Plasticidade Neuronal/fisiologia , Memória de Longo Prazo/fisiologia , Aplysia/fisiologiaRESUMO
Endometrial decidualization is critical to successful uterine receptivity and embryo implantation. Dysfunction of decidualization is associated with some pregnancy-related disorders, including miscarriage. Protein glycosylation is involved in many physiological and pathological processes. Protein O-fucosyltransferase 1 (poFUT1) is a key enzyme responsible for O-fucosylation biosynthesis on glycoproteins. Bone morphogenetic protein 1 (BMP1) is an essential glycoprotein in reproduction. However, the role and molecular mechanism of fucosylated BMP1 in endometrial stromal cell decidualization are still unknown. In the current study, we found that BMP1 contains a potential O-fucosylation site. Moreover, poFUT1 and BMP1 levels in the secretory phase are higher than those in the proliferative phase, and the highest level was observed in the human uterine tissues of early pregnancy, while a decrease of poFUT1 and BMP1 in the decidua was observed in miscarriage patients. Using human endometrial stromal cells (hESCs), we demonstrated that O-fucosylation of BMP1 was elevated after induced decidualization. Moreover, the increase of BMP1 O-fucosylation by poFUT1 promoted BMP1 secretion to the extracellular matrix, and more actively binds to CHRD. The binding of BMP1 and CHRD further released BMP4 originally bound to CHRD, and activated BMP/Smad signaling pathway, thereby accelerating the decidualization of human endometrial stromal cells. In summary, these results suggest that BMP1 O-fucosylation by poFUT1 could be a potential diagnostic and therapeutic target to predict miscarriage in early pregnancy examinations.
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Aborto Espontâneo , Gravidez , Feminino , Humanos , Glicosilação , Proteína Morfogenética Óssea 1/metabolismo , Endométrio/metabolismo , Transdução de Sinais/fisiologia , Células Estromais/metabolismo , Decídua/metabolismoRESUMO
Bone morphogenetic protein 1 (BMP1), a member of the astacin family of zinc-metalloproteases, proteolytically cleaves the low-density lipoprotein receptor (LDLR) within its ligand-binding domain, reducing the binding and cellular uptake of LDL-cholesterol. Here, we aimed to determine whether astacin proteases other than BMP1 may also cleave LDLR. Although human hepatocytes express all six astacin proteases, including the meprins and mammalian tolloid, we found through pharmacological inhibition and genetic knockdown that only BMP1 contributed to the cleavage of LDLR in its ligand-binding domain. We also found that the minimum amino acid change required to render mouse LDLR susceptible to cleavage by BMP1 is mutation at the P1' and P2 positions of the cleavage site. When expressed in cells, the resulting humanised-mouse LDLR internalised LDL-cholesterol. This work provides insight into the biological mechanisms regulating LDLR function.
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Proteína Morfogenética Óssea 1 , Peptídeo Hidrolases , Receptores de LDL , Animais , Humanos , Camundongos , Proteína Morfogenética Óssea 1/metabolismo , Colesterol , Hepatócitos/metabolismo , Ligantes , Lipoproteínas LDL/metabolismo , Mamíferos/metabolismo , Peptídeo Hidrolases/metabolismo , Proteólise , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMO
BMP signaling is critical for many biological processes. Therefore, small molecules that modulate BMP signaling are useful for elucidating the function of BMP signaling and treating BMP signaling-related diseases. Here, we performed a phenotypic screening in zebrafish to examine the in vivo effects of N-substituted-2-amino-benzoic acid analogs NPL1010 and NPL3008 and found that they affect BMP signaling-dependent dorsal-ventral (D-V) patterning and bone formation in zebrafish embryos. Furthermore, NPL1010 and NPL3008 suppressed BMP signaling upstream of BMP receptors. BMP1 cleaves Chordin, an antagonist of BMP, and negatively regulates BMP signaling. Docking simulations demonstrated that NPL1010 and NPL3008 bind BMP1. We found that NPL1010 and NPL3008 partially rescued the disruptions in the D-V phenotype caused by bmp1 overexpression and selectively inhibited BMP1-dependent Chordin cleavage. Therefore, NPL1010 and NPL3008 are potentially valuable inhibitors of BMP signaling that act through selective inhibition of Chordin cleavage.
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Proteínas Morfogenéticas Ósseas , Peixe-Zebra , Animais , Padronização Corporal/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Peixe-Zebra/genéticaRESUMO
Background: ADAMTS-13, a plasma metalloprotease, cleaves von Willebrand factor. ADAMTS-13 activity appears to be regulated through allosteric inhibition by its distal C-terminus. Objectives: The objective of this study was to better understand how domain-domain interactions may affect ADAMTS-13 conformations and functions. Methods: We performed deuterium-hydrogen exchange plus mass spectrometry to assess the number and rate of deuterium incorporation into various peptides of full-length ADAMTS-13 and its truncated variants. Results: Under physiological conditions, a bimodal distribution of deuterium incorporation was detected in the peptides from metalloprotease (217-230 and 282-304), cysteine-rich (446-482), and CUB (for complement C1r/C1s, Uegf, Bmp1) domains (1185-1214, 1313-1330, 1341-1347, 1358-1378, and 1393-1407) of full-length recombinant ADAMTS-13, but not of truncated variants. These results suggest that the full-length ADAMTS-13 undergoes conformational changes. On removal of the middle and distal C-terminal domains, the number and rate of deuterium incorporation were increased in the peptides from cysteine-rich (445-467, 467-482, and 495-503) and spacer domains (621-642 and 655-654) but decreased in the peptides from metalloprotease (115-124, 217-230, and 274-281). Moreover, most peptides, except for 217-230 and 1357-1376, exhibited a pD-dependent deuterium incorporation in the full-length ADAMTS-13, but not in the truncated variant (eg, MDTCS or T5C). These results further suggest that the bimodal deuterium incorporation observed in the peptides from the full-length ADAMTS-13 is the result of potential impact from the middle to distal C-terminal domains. Surface plasmon resonance revealed the direct binding interactions between the distal and proximal domains of ADAMTS-13. Conclusion: Our results provide novel insight on how intramolecular interactions may affect conformations of ADAMTS-13, thus regulating its proteolytic functions.
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Proteases are critical proteins involved in cleaving substrates that may impact biological pathways, cellular processes, or disease progression. In the biopharmaceutical industry, modulating the levels of protease activity is an important strategy for mitigating many types of diseases. While a variety of analytical tools exist for characterizing substrate cleavages, in vitro functional screening for antibody inhibitors of protease activity using physiologically relevant intact protein substrates remains challenging. In addition, detecting such large protein substrates with high heterogeneity using high-throughput mass spectrometry screening has rarely been reported in the literature with concerns for assay robustness and sensitivity. In this study, we established a peptide-based in vitro functional screening assay for antibody inhibitors of mouse bone morphogenic protein 1 (mBMP1) metalloprotease using a heterogeneous recombinant 66-kDa mouse Procollagen I alpha 1 chain (mProcollagen) substrate. We compared several analytical tools including capillary gel electrophoresis Western blot (CE-Western blot), as well as both intact protein and peptide-based mass spectrometry (MS) to quantitate the mBMP1 proteolytic activity and its inhibition by antibodies using this heterogeneous mProcollagen substrate. We concluded that the peptide-based mass spectrometry screening assay was the most suitable approach in terms of throughput, sensitivity, and assay robustness. We then optimized our mBMP1 proteolysis reaction after characterizing the enzyme kinetics using the peptide-based MS assay. This assay resulted in Z' values ranging from 0.6 to 0.8 from the screening campaign. Among over 1200 antibodies screened, IC50 characterization was performed on the top candidate hits, which showed partial or complete inhibitory activities against mBMP1.
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Peptídeos , Pró-Colágeno , Animais , Espectrometria de Massas , Camundongos , Peptídeo Hidrolases/metabolismo , Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Proteínas/metabolismo , Proteólise , Especificidade por SubstratoRESUMO
BACKGROUND: Anaplastic thyroid carcinoma (ATC) is an extremely aggressive solid tumor with no effective treatment at present. Because of the rapid growth and aggressiveness, nearly all patients die within six months after developing ATC. Hence, more research regarding novel therapeutic targets for ATC is urgently needed. METHODS: Single-cell RNA sequencing data and microarray data of ATC were retrieved from the Gene Expression Omnibus (GEO) database. Cell clustering was performed using the Seurat package. Then, differential expression and functional enrichment analyses were performed. Gene set enrichment analysis (GSEA) was further used to investigate the functional enrichment of lysyl oxidase (LOX) and bone morphogenetic protein-1 (BMP1). The expression levels of LOX and BMP1 were measured using quantitative real-time PCR and Western blot. LOX and BMP1 were knocked down using si-RNAs. Cell proliferation was evaluated by the CCK-8 and clone formation assays. Cell migration and invasion were assessed by the wound healing assay and Transwell assay, respectively. RESULTS: LOX was upregulated at the single-cell level, as well as in ATC tissues and cell lines. LOX knockdown significantly inhibited ATC cell proliferation. Furthermore, the migration and invasion of ATC cells were remarkably inhibited after LOX inhibition. In addition, BMP1 regulated LOX expression in 8505C cells, while BMP1 overexpression restored the LOX activity blocked by the LOX inhibitor BAPN. BMP1 could also induce the cell proliferation and metastasis of ATC. CONCLUSIONS: LOX/BMP1 mediates the malignant progression of ATC, highlighting the potential application of LOX/BMP1 in the treatment of ATC. This study provides new insights for efficient therapeutic agents based on the LOX/BMP1 axis.
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The correct balance between collagen synthesis and degradation is essential for almost every aspect of life, from development to healthy aging, reproduction and wound healing. When this balance is compromised by external or internal stress signals, it very often leads to disease as is the case in fibrotic conditions. Fibrosis occurs in the context of defective tissue repair and is characterized by the excessive, aberrant and debilitating deposition of fibril-forming collagens. Therefore, the numerous proteins involved in the biosynthesis of fibrillar collagens represent a potential and still underexploited source of therapeutic targets to prevent fibrosis. One such target is procollagen C-proteinase enhancer-1 (PCPE-1) which has the unique ability to accelerate procollagen maturation by BMP-1/tolloid-like proteinases (BTPs) and contributes to trigger collagen fibrillogenesis, without interfering with other BTP functions or the activities of other extracellular metalloproteinases. This role is achieved through a fine-tuned mechanism of action that is close to being elucidated and offers promising perspectives for drug design. Finally, the in vivo data accumulated in recent years also confirm that PCPE-1 overexpression is a general feature and early marker of fibrosis. In this review, we describe the results which presently support the driving role of PCPE-1 in fibrosis and discuss the questions that remain to be solved to validate its use as a biomarker or therapeutic target.
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Astacin-like proteinases (ALPs) are regulators of tissue and extracellular matrix (ECM) homeostasis. They convey this property through their ability to convert ECM protein pro-forms to functional mature proteins and by regulating the bioavailability of growth factors that stimulate ECM synthesis. The most studied ALPs in this context are the BMP-1/tolloid-like proteinases. The other subclass of ALPs in vertebrates - the meprins, comprised of meprin α and meprin ß - are emerging as regulators of tissue and ECM homeostasis but have so far been only limitedly investigated. Here, we functionally assessed the roles of meprins in skin wound healing using mice genetically deficient in one or both meprins. Meprin deficiency did not change the course of macroscopic wound closure. However, subtle but distinct contributions of meprins to the healing process and dermal homeostasis were observed. Loss of both meprins delayed re-epithelialization and reduced macrophage infiltration. Abnormal dermal healing and ECM regeneration was observed in meprin deficient wounds. Our analyses also revealed meprin α as one proteinase responsible for maturation of pro-collagen VII to anchoring fibril-forming-competent collagen VII in vivo. Collectively, our study identifies meprins as subtle players in skin wound healing.
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Bone morphogenic proteins (BMPs) are important growth regulators in embryogenesis and postnatal homeostasis. Their tight regulation is crucial for successful embryonic development as well as tissue homeostasis in the adult organism. BMP inhibition by natural extracellular biologic antagonists represents the most intensively studied mechanistic concept of BMP growth factor regulation. It was shown to be critical for numerous developmental programs, including germ layer specification and spatiotemporal gradients required for the establishment of the dorsal-ventral axis and organ formation. The importance of BMP antagonists for extracellular matrix homeostasis is illustrated by the numerous human connective tissue disorders caused by their mutational inactivation. Here, we will focus on the known functional interactions targeting BMP antagonists to the ECM and discuss how these interactions influence BMP antagonist activity. Moreover, we will provide an overview about the current concepts and investigated molecular mechanisms modulating BMP inhibitor function in the context of development and disease.
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OBJECTIVES: Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; extra-skeletal features in OI include blue sclerae, dentinogenesis imperfecta, skin laxity and joint hyper-extensibility. Most patients with OI are thought to have a low bone mass but contrary to expectations there are certain forms of OI with high bone mass which this study explores in further detail. METHOD: A cohort of n = 6 individuals with pathogenic variants in BMP1 and the C-propeptide cleavage variants in COL1A1 were included in this study. Detailed clinical and radiological phenotyping was done and correlated with genotype to identify patterns of clinical presentation and fracture history in this cohort of patients. This data was compared to previously reported literature in this group. RESULTS: 2 patients with BMP1 and 4 patients with pathogenic variants in C-propeptide region in COL1A1 were deep-phenotyped as part of this study and 1 patient with C-propeptide variant in COL1A1, showed low bone mineral density. In those with an elevated bone mineral density, this became even more apparent on bisphosphonate therapy. Patients in this cohort had variable clinical presentation ranging from antenatal presentation to more of an insidious course resulting in later confirmation of genetic diagnosis up to 19 years of age. CONCLUSIONS: Patients with pathogenic variants in the C-propeptide region of COL1A1/A2 and BMP1 appear to have a high bone mass phenotype with increased sensitivity to bisphosphonate therapy. It is important to closely monitor patients with these genotypes to assess their response to therapy and tailor their treatment regime accordingly.
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BACKGROUND: Osteogenesis imperfecta (OI) is a rare heritable bone disorder that is characterised by increased bone fragility and recurrent fractures. To date, only 19 OI patients have been reported, as caused by BMP1 gene mutations, worldwide. Here, we report a patient with a BMP1 gene mutation to explore the relationship between genotype and phenotype, and the patient was followed up for 4 years. METHODS: Detailed clinical features were collected, and BMP1 mutational analysis was performed by next-generation sequencing and Sanger sequencing. RESULTS: The patient had recurrent fractures, low bone mass, bone deformities and growth retardation but did not have hearing loss or dentinogenesis imperfecta. Next-generation sequencing and Sanger sequencing revealed a heterozygous novel missense variant (c.362C>T in exon 3, p.Ala121Val) and a heterozygous novel deletion mutation (c.1252delA in exon 10, p.Ser418AlafsX22). The parents of the proband were heterozygous carriers of these mutations. The patient received regular weekly treatment of 70 mg oral alendronate for 3 years, and her BMD Z-score for the femur significantly increased from -1.3 to 0.9 at L1-4 and from -1.7 to -0.1. She had no fracture during 4 years of follow-up. CONCLUSION: We discovered two heterozygous novel mutations in an OI patient with BMP1 gene mutations, expanding the spectrum of gene mutations in OI.
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Proteína Morfogenética Óssea 1/genética , Mutação de Sentido Incorreto , Osteogênese Imperfeita/genética , Alendronato/administração & dosagem , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Criança , Feminino , Homozigoto , Humanos , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/patologiaRESUMO
Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. BMP1 variants have been reported in the rare OI type XIII, specifically referred to herein as BMP1-associated autosomal recessive (AR) OI. We report the clinical presentation and diagnostic evaluation of a patient found to have a novel homozygous variant in BMP1. We also provide an overview of reported BMP1 variants to date, with discussion focusing on the use of bisphosphonate therapy in these patients. A 7-year-old male with speech and motor delay sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6, he developed severe back pain after a fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3, and L5 were identified. Total hip BMD was generous (adjusted Z-score* = 1.76), and femoral neck BMD was high (adjusted Z-score* = 2.67). VCFs precluded assessment of lumbar spine BMD. Genetic analysis identified a homozygous missense variant in exon 4 of BMP1 (c.C505T; p.Arg169Cys). Unlike most forms of OI, patients with BMP1-associated AR OI may have normal or paradoxically increased BMD, making BMD and fracture risk correlation difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and underlying bone pathology, often in the setting of increased BMD, complicate management. HR-pQCT assessment of bone microarchitecture and quality may aid in the decision of BP therapy and subsequent monitoring. Evidence is limited with respect to the effectiveness of BP in this rare form of OI. *Z-score was adjusted for height Z-score.
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Fraturas Ósseas , Fraturas por Compressão , Osteogênese Imperfeita , Fraturas da Coluna Vertebral , Densidade Óssea/genética , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Humanos , Masculino , Mutação , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Fenótipo , Fraturas da Coluna Vertebral/genéticaRESUMO
Bone morphogenetic protein 1 (BMP1) is a secreted metalloprotease of the astacin M12A family of bone morphogenetic proteins (BMPs). BMP1 activates transforming growth factor-ß (TGF-ß) and BMP signaling pathways by proteolytic cleavage, which has dual roles in gastrointestinal tumor development and progression.TGF-ß promotes invasion and metastasis of gastric cancer (GC) by the help of BMP1, so upregulation of the BMP1 may increase cancer invasiveness in GC. In this study,the transcriptional expression, mutations, survival rate, TFs, miRNAs, gene ontology, and signaling pathways of BMP1 were analyzed by using different web servers. We found higher transcriptional and clinicopathological characteristics expression compared to normal tissues, worsening survival rate in GC. We detected 25 missenses, 15 truncating mutations, 23 TFs, and 8 miRNAs. Finally, we identified and analyzed the co-expressed genes and found that the leukemia inhibitory factor is the most positively correlated gene. The gene ontological features and signaling pathways involved in GC development were evaluated as well. We believe that this study will provide a basis for BMP1 to be a significant biomarker for human GC prognosis.
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Biomarcadores Tumorais/genética , Proteína Morfogenética Óssea 1/genética , Neoplasias Gástricas/genética , Biomarcadores Tumorais/metabolismo , Proteína Morfogenética Óssea 1/metabolismo , Biologia Computacional , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Mutação , Prognóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para CimaRESUMO
PURPOSE: To investigate the potential role of Bone morphogenetic protein 1 (BMP1) in endometriosis lesions. METHODS: Endometriosis model in mice was established. The expression of BMP1-3 expression in mice of endometriosis lesions was evaluated. The effect of the treatment with anti-BMP1 antibodies on the expression of MMP2, MMP9, TGF-ß, IL-17, IL-1ß, Col1a1 and Col1a2 levels in mice was evaluated. In endometriosis cell model, the expression of IL-17, IL-1ß, MMP2 and MMP9 levels and MIF, YWHAZ, ß-catenin and CAP39 mRNA levels was also detected. RESULTS: The expression of BMP1-3 expression was upregulated in mice of endometriosis lesions (p < 0.01). Treatment with anti-BMP1 antibodies dose-dependently reduced MMP2, MMP9, TGF-ß, IL-17, IL-1ß, Col1a1 and Col1a2 levels in mice (p < 0.01). Treatment with anti-BMP1 antibodies suppressed TGF-ß/PI3K/Akt signaling pathway. In vitro cell, si-BMP1 suppressed TGF-ß/PI3K/Akt signaling pathway. CONCLUSION: The data support the hypothesis that the inhibition of BMP1 is involved in the pathogenesis of endometriosis lesions.