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Developmental Dynamics : An Official... Apr 2015The submucosal glands (SMGs) of the respiratory system are specialized structures essential for maintaining airway homeostasis. The significance of SMGs is highlighted... (Review)
Review
BACKGROUND
The submucosal glands (SMGs) of the respiratory system are specialized structures essential for maintaining airway homeostasis. The significance of SMGs is highlighted by their involvement in respiratory diseases such as cystic fibrosis, asthma and chronic bronchitis, where their phenotype and function are severely altered. Uncovering the normal development of the airway SMGs is essential to elucidate their role in these disorders, however, very little is known about the cellular mechanisms and intracellular signals involved in their morphogenesis.
RESULTS
This review describes in detail the embryonic developmental journey of the nasal SMGs and the postnatal development of the tracheal SMGs in the mouse. Current knowledge of the genes and signalling molecules involved in SMG organogenesis is also explored.
CONCLUSION
Here we review the temporal localisation and development of the murine respiratory glands in the hope of stimulating further research into the mechanisms required for successful SMG patterning and function.
Topics: Adipocytes; Animals; Animals, Genetically Modified; Basement Membrane; Collagen Type IV; Drosophila melanogaster; Exocrine Glands; Extracellular Matrix; Hemocytes; Mice; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Mutation; Necrosis; Osteonectin; Phenotype; Respiratory System; Temperature
PubMed: 25648514
DOI: 10.1002/dvdy.24250 -
Journal of Orthopaedic Surgery and... Oct 2023The aim of this study was to investigate whether Osteonectin/Secreted protein acidic and rich in cysteine (ON/SPARC) had a two-way dose-dependent regulatory effect on...
OBJECTIVE
The aim of this study was to investigate whether Osteonectin/Secreted protein acidic and rich in cysteine (ON/SPARC) had a two-way dose-dependent regulatory effect on osteoblast mineralization and its molecular mechanism.
METHODS
Initially, different concentrations of ON were added in osteoblasts, and the gene of bone sialoprotein (BSP), osteocalcin (OCN), osteopontin (OPN) and alkaline phosphatase (ALP) were detected using reverse-transcription quantitative polymerase chain reaction (RT-PCR). Secondly, based on the above results, the Optima and inhibitory concentration of ON for osteoblast mineralization were determined and regrouped, the Control group was also set up, and the gene detections of Collagen 1 (Col 1), Discoidin domain receptor 2 (DDR2) and p38 mitogen‑activated protein kinase were added using RT-PCR. In the third stage of the experiment, osteoblasts were pretreated with 0.4Mm ethyl-3,4-dihydroxybenzoate (DHB) (a specific inhibitor of collagen synthesis) for 3 h before adding the optima SPARC, the gene and protein expressions of OCN, OPN, BSP, ALP, DDR2, ALP, Col 1, DDR2 and P38 were detected by RT‑qPCR and western blot analysis, and the mineralized nodules were observed by alizarin red staining.
RESULTS
The results showed that the expression of OCN, OPN, BSP, ALP, DDR2, ALP, Col 1, DDR2 and P38 genes and proteins in osteoblasts were significantly enhanced by 1 ug/ml ON, 100 ug/ml ON or 1 ug/ml ON added with 3,4 DHB significantly inhibited the expressions of DDR2, P38 and the above-mentioned mineralization indexes, and significantly reduced the formation of mineralized nodules.
CONCLUSION
This study suggested that ON had a bidirectional dose-dependent regulatory effect on osteoblast mineralization, and the activation of P38 pathway by collagen binding to DDR2 was also an important molecular mechanism.
Topics: Humans; Osteonectin; Osteocalcin; Calcinosis; Integrin-Binding Sialoprotein; Collagen; Osteoblasts; Cell Differentiation; Osteogenesis
PubMed: 37807073
DOI: 10.1186/s13018-023-04250-1 -
Tissue Engineering. Part A Apr 2022Failure to regenerate the gradient tendon-bone interface of the enthesis results in poor clinical outcomes for surgical repair. The goal of this study was to evaluate...
Failure to regenerate the gradient tendon-bone interface of the enthesis results in poor clinical outcomes for surgical repair. The goal of this study was to evaluate the potential of composite cell sheets for engineering of the tendon-bone interface to improve regeneration of the functionally graded tissue. We hypothesize that stacking cell sheets at early stages of differentiation into tenogenic and osteogenic progenitors will create a composite structure with integrated layers. Cell sheets were fabricated on methyl cellulose and poly(N-isopropylacrylamide) thermally reversible polymers with human adipose-derived stem cells and differentiated into progenitors of tendon and bone with chemical induction media. Tenogenic and osteogenic cell sheets were stacked, and the engineered tendon-bone interface (TM-OM) was characterized in comparison to stacked cell sheet controls cultured in basal growth medium (GM-GM), osteogenic medium (OM-OM), and tenogenic medium (TM-TM). Samples were characterized by histology, quantitative real-time polymerase chain reaction, and immunofluorescent staining for markers of tendon, fibrocartilage, and bone including mineralization, scleraxis, tenomodulin, , , , osteonectin, and osterix. After 1 week co-culture in basal growth medium, TM-OM cell sheets formed a tissue construct with integrated layers expressing markers of tendon, mineralized fibrocartilage, and bone with a spatial gradient in RUNX2 expression. Tenogenic cell sheets had increased expression of scleraxis and tenomodulin. Osteogenic cell sheets exhibited mineralization 1 week after stacking and upregulation of osterix and osteonectin. Additionally, in the engineered interface, there was significantly increased gene expression of and , indicative of endochondral ossification. These results highlight the potential for composite cell sheets fabricated with adipose-derived stem cells for engineering of the tendon-bone interface. Impact statement This study presents a method for fabrication of the tendon-bone interface using stacked cell sheets of tenogenic and osteogenic progenitors differentiated from human adipose-derived mesenchymal stem cells, resulting in a composite structure expressing markers of tendon, mineralized fibrocartilage, and bone. This work is an important step toward regeneration of the biological gradient of the enthesis and demonstrates the potential for engineering complex tissue interfaces from a single autologous cell source to facilitate clinical translation.
Topics: Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Humans; Mesenchymal Stem Cells; Osteonectin; Tendons; Tissue Engineering
PubMed: 34476994
DOI: 10.1089/ten.TEA.2021.0072 -
Cardiovascular Research Feb 2022Aortic valve calcification is more prevalent in chronic kidney disease accompanied by hypercalcemia. Secreted protein acidic and rich in cysteine (SPARC)-related modular...
AIMS
Aortic valve calcification is more prevalent in chronic kidney disease accompanied by hypercalcemia. Secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) is a regulator of BMP2 signalling, but the role of SMOC1 in aortic valve calcification under different conditions has not been studied. This study aimed to investigate the roles of SMOC1 in aortic valve calcification under normal and high calcium conditions, focusing on the effects on aortic valve interstitial cells (AVICs).
METHODS AND RESULTS
SMOC1 was expressed by aortic valve endothelial cells and secreted into the extracellular matrix in non-calcific valves and downregulated in calcific aortic valves. In vitro studies demonstrated that HUVEC secreted SMOC1 could enter the cytoplasm of AVICs. Overexpression of SMOC1 attenuated warfarin-induced AVIC calcification but promoted high calcium/phosphate or vitamin D-induced AVIC and aortic valve calcification by regulating BMP2 signalling both in vitro and in vivo. Co-immunoprecipitation revealed that SMOC1 binds to BMP receptor II (BMPR-II) and inhibits BMP2-induced phosphorylation of p38 (p-p38) via amino acids 372-383 of its EF-hand calcium-binding domain. Inhibition of p-p38 by the p38 inhibitor SB203580 blocked the effects of SMOC1 on BMP2 signalling and AVIC calcification induced by high calcium/phosphate medium. In high-calcium-treated AVICs, SMOC1 lost its ability to bind to BMPR-II, but not to caveolin-1, promoting p-p38 and cell apoptosis due to increased expression of BMPR-II and enhanced endocytosis.
CONCLUSIONS
These observations support that SMOC1 works as a dual-directional modulator of AVIC calcification by regulating p38-dependent BMP2 signalling transduction according to different extracellular calcium concentrations.
Topics: Aortic Valve; Aortic Valve Stenosis; Bone Morphogenetic Protein Receptors, Type II; Calcium; Cells, Cultured; Endothelial Cells; Humans; Osteonectin; Phosphorylation; p38 Mitogen-Activated Protein Kinases
PubMed: 33757126
DOI: 10.1093/cvr/cvab107 -
Developmental Biology Nov 2017Collagen IV networks endow basement membranes (BMs) with remarkable tensile strength and function as morphoregulatory substrata for diverse tissue-specific developmental... (Review)
Review
Collagen IV networks endow basement membranes (BMs) with remarkable tensile strength and function as morphoregulatory substrata for diverse tissue-specific developmental events. A complex repertoire of intracellular and extracellular molecular interactions are required for collagen IV secretion and supramolecular assembly into BMs. These include intracellular chaperones such as Heat shock protein 47 (Hsp47) and the chaperone-binding trafficking protein Transport and Golgi organization protein 1 (Tango1). Mutations in these proteins lead to compromised collagen IV protomer stability and secretion, leading to defective BM assembly and function. In addition to intracellular chaperones, a role for extracellular chaperones orchestrating the transport, supramolecular assembly, and architecture of collagen IV in BM is emerging. We present evidence derived from evolutionarily distant model organisms that supports an extracellular collagen IV chaperone-like activity for the matricellular protein SPARC (Secreted Protein, Acidic, Rich in Cysteine). Loss of SPARC disrupts BM homeostasis and compromises tissue biomechanics and physiological function. Thus, the combined contributions of intracellular and extracellular collagen IV-associated chaperones and chaperone-like proteins are critical to ensure proper secretion and stereotypic assembly of collagen IV networks in BMs.
Topics: Animals; Basement Membrane; Collagen Type IV; Evolution, Molecular; Humans; Osteonectin; Protein Folding; Protein Transport
PubMed: 28982537
DOI: 10.1016/j.ydbio.2017.09.037 -
Kidney International Sep 2021Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently...
Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.
Topics: Biomarkers; Cadherins; Calcium-Binding Proteins; Disease Progression; Eye Proteins; Fibrosis; Humans; Kidney; Nerve Growth Factors; Osteonectin; Prospective Studies; Renal Insufficiency, Chronic; Serpins
PubMed: 34051265
DOI: 10.1016/j.kint.2021.04.037 -
Journal of Biomedical Science Sep 2020The use of in silico strategies to develop the structural basis for a rational optimization of glycan-protein interactions remains a great challenge. This problem... (Review)
Review
The use of in silico strategies to develop the structural basis for a rational optimization of glycan-protein interactions remains a great challenge. This problem derives, in part, from the lack of technologies to quantitatively and qualitatively assess the complex assembling between a glycan and the targeted protein molecule. Since there is an unmet need for developing new sugar-targeted therapeutics, many investigators are searching for technology platforms to elucidate various types of molecular interactions within glycan-protein complexes and aid in the development of glycan-targeted therapies. Here we discuss three important technology platforms commonly used in the assessment of the complex assembly of glycosylated biomolecules, such as glycoproteins or glycosphingolipids: Biacore analysis, molecular docking, and molecular dynamics simulations. We will also discuss the structural investigation of glycosylated biomolecules, including conformational changes of glycans and their impact on molecular interactions within the glycan-protein complex. For glycoproteins, secreted protein acidic and rich in cysteine (SPARC), which is associated with various lung disorders, such as chronic obstructive pulmonary disease (COPD) and lung cancer, will be taken as an example showing that the core fucosylation of N-glycan in SPARC regulates protein-binding affinity with extracellular matrix collagen. For glycosphingolipids (GSLs), Globo H ceramide, an important tumor-associated GSL which is being actively investigated as a target for new cancer immunotherapies, will be used to demonstrate how glycan structure plays a significant role in enhancing angiogenesis in tumor microenvironments.
Topics: Glycosylation; Molecular Docking Simulation; Molecular Dynamics Simulation; Osteonectin; Polysaccharides; Protein Binding
PubMed: 32900381
DOI: 10.1186/s12929-020-00684-5 -
Cell Communication and Signaling : CCS Mar 2024Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be... (Review)
Review
Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD-like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.
Topics: Humans; NF-kappa B; Osteonectin; TOR Serine-Threonine Kinases; Inflammation; Ossification, Heterotopic
PubMed: 38439078
DOI: 10.1186/s12964-024-01533-w -
Scientific Reports Sep 2022Fracture nonunion is a common and challenging complication. Although direct current stimulation has been suggested to promote fracture healing, differences in cell...
Fracture nonunion is a common and challenging complication. Although direct current stimulation has been suggested to promote fracture healing, differences in cell density near the positive and negative electrodes have been reported during direct current stimulation. This study aimed to explore the effects of these differences on osteoblast proliferation and fracture healing. MC3T3-E1 cells were stimulated by positive and negative charges to observe cell proliferation, apoptosis, and osteogenic factor expression in vitro, while positive and negative charges were connected to the Kirschner wires of the fractures in an in vivo double-toe fracture model in New Zealand white rabbits and fracture healing was assessed in digital radiography (DR) examinations performed on days 1, 15, 30. Bone tissue samples of all rabbits were analysed histologically after the last examination. The results showed that in comparison with the control group, after DC stimulation, the number of cells near the positive electrode decreased significantly (P < 0.05), apoptosis increased (P < 0.05), the expression of osteocalcin, osteoblast-specific genes, and osteonectin decreased significantly near the positive electrode (P < 0.05) and increased significantly at the negative electrode (P < 0.05). The fracture at the positive electrode junction of New Zealand white rabbits did not heal. Histomorphological analysis showed more bone trabeculae and calcified bone in the bone tissue sections of the control group and the negative electrode group than in the positive electrode group. The bone trabeculae were thick and showed good connections. However, positive charge inhibited osteoblast proliferation and a positive charge at fracture sites did not favour fracture healing. Thus, a positive charge near the fracture site may be a reason for fracture nonunion.
Topics: Animals; Fracture Healing; Fractures, Bone; Fractures, Ununited; Osteocalcin; Osteogenesis; Osteonectin; Rabbits
PubMed: 36151271
DOI: 10.1038/s41598-022-20153-3 -
Cellular and Molecular Life Sciences :... Jan 2014Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte... (Review)
Review
Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte migration and differentiation are complex and have not been fully established. Current literature suggests that platelet-derived growth factor/platelet-derived growth factor receptor-β, sphingosine 1-phosphate/endothelial differentiation gene-1, angiopoietin-1/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, angiopoietin-2/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, transforming growth factor β/activin receptor-like kinase 1, transforming growth factor β/activin receptor-like kinase 5, Semaphorin-3A/Neuropilin, and matrix metalloproteinase activity regulate the recruitment of pericytes to nascent vessels. Interestingly, many of these pathways are directly affected by secreted protein acidic and rich in cysteine (SPARC). Here, we summarize the function of these factors in pericyte migration and discuss if and how SPARC might influence these activities and thus provide an additional layer of control for the recruitment of vascular support cells. Additionally, the consequences of targeted inhibition of pericytes in tumors and the current understanding of pericyte recruitment in pathological environments are discussed.
Topics: Cell Movement; Humans; Intercellular Signaling Peptides and Proteins; Metalloendopeptidases; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Osteonectin; Pericytes; Protein Kinases; Signal Transduction; Vesicular Transport Proteins
PubMed: 23912898
DOI: 10.1007/s00018-013-1432-z