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Immunity Sep 2022The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein,...
The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.
Topics: Aging; Humans; Inflammation; Interferons; Macrophages; Osteonectin
PubMed: 35963236
DOI: 10.1016/j.immuni.2022.07.007 -
American Journal of Physiology. Cell... Aug 2022Megakaryocyte hyperplasia associated with myeloproliferative neoplasms commonly leads to abnormal bone tissue deposition in the bone marrow, known as osteosclerosis. In...
Megakaryocyte hyperplasia associated with myeloproliferative neoplasms commonly leads to abnormal bone tissue deposition in the bone marrow, known as osteosclerosis. In this study, we aimed to synthesize the known proteomics literature describing factors released by megakaryocytes and platelets and to examine if any of the secreted factors have a known ability to stimulate the bone-forming cells, osteoblasts. Using a systematic search of Medline, we identified 77 articles reporting on factors secreted by platelets and megakaryocytes. After a full-text screening and analysis of the studies, we selected seven papers that reported proteomics data for factors secreted by platelets from healthy individuals. From 60 proteins reported in at least two studies, we focused on 23 that contained a putative signal peptide, which we searched for a potential osteoblast-stimulatory function. From nine proteins with a positive effect on osteoblast formation and function, two extracellular matrix (ECM) proteins, secreted protein acidic and rich in cysteine (SPARC) and tissue inhibitor of metalloproteinase-1 (TIMP1), and three cellular proteins with known extracellular function, the 70-kDa heat shock protein (HSP70), thymosin-β4 (TB4), and super dismutase (SOD), were identified as hypothetical candidate molecules to be examined as potential mediators in mouse models of osteomyelofibrosis. Thus, careful analysis of prior literature can be beneficial in assisting the planning of future experimental studies.
Topics: Animals; Blood Platelets; Extracellular Matrix Proteins; Mice; Osteoblasts; Osteonectin; Secretome; Tissue Inhibitor of Metalloproteinase-1
PubMed: 35675640
DOI: 10.1152/ajpcell.00187.2022 -
The Journal of Clinical Investigation Oct 2023The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in...
The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.
Topics: Animals; Humans; Mice; Adipose Tissue; Diet, High-Fat; Inflammasomes; Inflammation; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Osteonectin
PubMed: 37781916
DOI: 10.1172/JCI169173 -
Annals of Oncology : Official Journal... Nov 2021
Topics: Humans; Lymphoma; Macrophages; Osteonectin
PubMed: 34492312
DOI: 10.1016/j.annonc.2021.08.2152 -
Matrix Biology : Journal of the... 2016Secreted protein acidic and rich in cysteine (SPARC/osteonectin/BM40) is one of the most abundant non-collagenous protein expressed in mineralized tissues. This review... (Review)
Review
Secreted protein acidic and rich in cysteine (SPARC/osteonectin/BM40) is one of the most abundant non-collagenous protein expressed in mineralized tissues. This review will focus on elucidating functional roles of SPARC in bone formation building upon results from non-mineralized cells and tissues, the phenotype of SPARC-null bones, and recent discoveries of human diseases with either dysregulated expression of SPARC or mutations in the gene encoding SPARC that give rise to bone pathologies. The capacity of SPARC to influence pathways involved in extracellular matrix assembly such as procollagen processing and collagen fibril formation as well as the capacity to influence osteoblast differentiation and osteoclast activity will be addressed. In addition, the potential for SPARC to regulate cross-linking of extracellular matrix proteins by members of the transglutaminase family of enzymes is explored. Elucidating defined biological functions of SPARC in terms of bone formation and turnover are critical. Further insight into specific cellular mechanisms involved in the formation and homeostasis of mineralized tissues will lead to a better understanding of disease progression.
Topics: Animals; Bone and Bones; Calcification, Physiologic; Cell Differentiation; Extracellular Matrix; Gene Expression Regulation; Humans; Mutation; Osteoblasts; Osteoclasts; Osteogenesis Imperfecta; Osteonectin; Osteoporosis; Transglutaminases
PubMed: 26851678
DOI: 10.1016/j.matbio.2016.02.001 -
Experimental Cell Research Aug 2023Fibrotic scar is a severe side effect of trabeculectomy, resulting in unsatisfactory outcomes for glaucoma surgery. Accumulating evidence showed human Tenon's...
BACKGROUND
Fibrotic scar is a severe side effect of trabeculectomy, resulting in unsatisfactory outcomes for glaucoma surgery. Accumulating evidence showed human Tenon's fibroblasts (HTFs) play an important role in fibrosis formation. We previously reported that the aqueous level of secreted protein acidic and rich in cysteine (SPARC) was higher in the patients with primary angle closure glaucoma, which was associated with the failure of trabeculectomy. In this study, the potential effect and mechanism of SPARC in promoting fibrosis were explored by using HTFs.
METHODS
HTFs were employed in this study and examined under a phase-contrast microscope. Cell viability was determined by CCK-8. The expressions of SPARC-YAP/TAZ signaling and the fibrosis-related markers were examined with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence, subcellular fractionation was conducted to further determined the variation of YAP and phosphorylated YAP. The differential gene expressions were analyzed with RNA sequencing (RNAseq), followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses.
RESULTS
Exogenous SPARC induced HTFs-myofibroblast transformation, as evidenced by the increased expression of α-SMA, collagen I and fibronectin in both protein and mRNA levels. SPARC knockdown decreased the expressions of the above genes in TGF-β2-treated HTFs. KEGG analysis showed that the Hippo signaling pathway was mostly enriched. SPARC treatment increased the expressions of YAP, TAZ, CTGF and CYR61 as well as enhanced YAP translocation from cytoplasm to nucleus, and decreased the phosphorylation of YAP and LAST1/2, which was reversed by SPARC knockdown. Knockdown of YAP1 decreased the fibrosis-related markers, such as α-SMA, collagen I and Fibronectin, in SPARC-treated HTFs.
CONCLUSIONS
SPARC induced HTFs-myofibroblast transformation via activating YAP/TAZ signaling. Targeting SPARC-YAP/TAZ axis in HTFs might provide a novel strategy for inhibiting fibrosis formation after trabeculectomy.
Topics: Humans; Myofibroblasts; Fibronectins; Osteonectin; Fibroblasts; Collagen Type I; Fibrosis; Cells, Cultured
PubMed: 37225012
DOI: 10.1016/j.yexcr.2023.113649 -
American Journal of Physiology. Cell... Sep 2021In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscles (myokines). However, how... (Review)
Review
In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscles (myokines). However, how myokines affect the maturation, maintenance, and regeneration of tendons as a function of age is completely unstudied. Here we discuss the role of four myokines-fibroblast growth factors (FGF), myostatin, the secreted protein acidic and rich in cysteine (SPARC) miR-29-in tendon development and hypothesize a role for these factors in the progressive changes in tendon structure and function as a result of muscle wasting (disuse, aging, and disease). Because of the close relationship between mechanical loading and muscle and tendon regulation, disentangling muscle-tendon cross talk from simple mechanical loading is experimentally quite difficult. Therefore, we propose an experimental framework that hopefully will be useful in demonstrating muscle-tendon cross talk in vivo. Though understudied, the promise of a better understanding of muscle-tendon cross talk is the development of new interventions that will improve tendon development, regeneration, and function throughout the lifespan.
Topics: Aging; Animals; Biomechanical Phenomena; Exosomes; Fibroblast Growth Factors; Gene Expression Regulation; Humans; MicroRNAs; Muscle Cells; Muscle, Skeletal; Muscular Atrophy; Myostatin; Osteonectin; Signal Transduction; Tendons
PubMed: 34319830
DOI: 10.1152/ajpcell.00260.2021 -
WormBook : the Online Review of C.... Sep 2005Basement membranes are thin, specialized extracellular matrices surrounding most tissues in all metazoans. The compositions and functions of basement membranes have... (Review)
Review
Basement membranes are thin, specialized extracellular matrices surrounding most tissues in all metazoans. The compositions and functions of basement membranes have generally been well conserved throughout the subkingdom. Genetic analyses of basement membrane components in C. elegans have provided insights into their assembly and functions during development. Immuno- or GFP-tagged localization studies have shown that basement membranes on different tissues, or even sub-regions of tissues, contain different sets of proteins or alternatively spliced isoforms of them. Several components, including laminin, perlecan, type IV collagen and possibly osteonectin/SPARC, are essential for completion of embryogenesis, being necessary for tissue organization and structural integrity. In contrast, type XVIII collagen and nidogen are not required for viability but primarily influence organization of the nervous system. All of these proteins, with the exception of nidogen and the addition of fibulin, have roles of varying degree in morphogenesis of the gonad. A major family of cellular receptors for basement membrane proteins, the integrins, have also been characterized in C. elegans. As one might expect, integrins have been shown to function in many of the same processes as their potential ligands, the basement membrane components. While much remains to be explored, studies of basement membranes in C. elegans have been highly informative and hold great promise for improving our understanding of how these structures are assembled and how they function in development.
Topics: Animals; Basement Membrane; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcium-Binding Proteins; Collagen; Heparan Sulfate Proteoglycans; Humans; Integrins; Laminin; Membrane Glycoproteins; Membrane Proteins; Osteonectin; Receptors, Laminin
PubMed: 18050423
DOI: 10.1895/wormbook.1.16.1 -
International Journal of Environmental... Jul 2022Currently, researchers are focused on the study of cytokines as predictive biomarkers of peri-implantitis (PI) in order to obtain an early diagnosis and prognosis, and... (Observational Study)
Observational Study
Currently, researchers are focused on the study of cytokines as predictive biomarkers of peri-implantitis (PI) in order to obtain an early diagnosis and prognosis, and for treatment of the disease. The aim of the study was to characterize the peri-implant soft and hard tissues in patients with a peri-implantitis diagnosis. A descriptive observational study was conducted. Fifteen soft tissue (ST) samples and six peri-implant bone tissue (BT) samples were obtained from 13 patients who were diagnosed with peri-implantitis. All the samples were processed and embedded in paraffin for histological and immunohistochemical analyses. A descriptive and quantitative analysis of mast cells and osteocytes, A proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF), osteonectin (ON), and ∝-smooth muscle actin (∝-SMA) was performed. We observed the presence of mast cells in peri-implant soft tissue in all samples (mean 9.21 number of mast cells) and osteocytes in peri-implant hard tissue in all samples (mean 37.17 number of osteocytes). The expression of APRIL-ST was 32.17% ± 6.39%, and that of APRIL-BT was 7.09% ± 5.94%. The BAFF-ST expression was 17.26 ± 12.90%, and the BAFF-BT was 12.16% ± 6.30%. The mean percentage of ON was 7.93% ± 3.79%, and ∝-SMA was 1.78% ± 3.79%. It was concluded that the expression of APRIL and BAFF suggests their involvement in the bone resorption observed in peri-implantitis. The lower expression of osteonectin in the peri-implant bone tissue can also be associated with a deficiency in the regulation of bone remodeling and the consequent peri-implant bone loss.
Topics: Biomarkers; Bone Resorption; Cytokines; Humans; Osteonectin; Peri-Implantitis
PubMed: 35886240
DOI: 10.3390/ijerph19148388 -
Matrix Biology : Journal of the... Jul 2014Glaucoma is an optic neuropathy affecting approximately 60million people worldwide and is the second most common cause of irreversible blindness. Elevated intraocular... (Review)
Review
Glaucoma is an optic neuropathy affecting approximately 60million people worldwide and is the second most common cause of irreversible blindness. Elevated intraocular pressure (IOP) is the main risk factor for developing glaucoma and is caused by impaired aqueous humor drainage through the trabecular meshwork (TM) and Schlemm's canal (SC). In primary open angle glaucoma (POAG), this elevation in IOP in turn leads to deformation at the optic nerve head (ONH) specifically at the lamina cribrosa (LC) region where there is also a deposition of extracellular matrix (ECM) molecules such as collagen and fibronectin. Matricellular proteins are non-structural secreted glycoproteins that help cells communicate with their surrounding ECM. This family of proteins includes connective tissue growth factor (CTGF), also known as CCN2, thrombospondins (TSPs), secreted protein acidic and rich in cysteine (SPARC), periostin, osteonectin, and Tenascin-C and -X and other ECM proteins. All members appear to play a role in fibrosis and increased ECM deposition. Most are widely expressed in tissues particularly in the TM and ONH and deficiency of TSP1 and SPARC have been shown to lower IOP in mouse models of glaucoma through enhanced outflow facility. The role of these proteins in glaucoma is emerging as some have an association with the pathophysiology of the TM and LC regions and might therefore be potential targets for therapeutic intervention in glaucoma.
Topics: Animals; Aqueous Humor; Cell Adhesion Molecules; Connective Tissue Growth Factor; Drug Delivery Systems; Extracellular Matrix Proteins; Glaucoma; Humans; Intraocular Pressure; Mice; Models, Biological; Osteonectin; Thrombospondins; Trabecular Meshwork
PubMed: 24727033
DOI: 10.1016/j.matbio.2014.03.007