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The International Journal of... Dec 1999SPARC (Secreted ProteinAcidic and Rich in Cysteine) is a prototype of a family of biologically active glycoproteins that bind to cells and to extracellular matrix (ECM)... (Review)
Review
SPARC (Secreted ProteinAcidic and Rich in Cysteine) is a prototype of a family of biologically active glycoproteins that bind to cells and to extracellular matrix (ECM) components. It is expressed spatially and temporally during embryogenesis, tissue remodeling and repair. SPARC is a modular protein (34 kDa) comprised of three structural domains, one or more of which are implicated in the regulation of cell adhesion, proliferation, matrix synthesis/turnover. Rapid proteolysis of SPARC by extracellular proteases accounts for its transient detection in the extracellular environment. The proposed roles of SPARC in the development of cataracts and the regulation of angiogenesis during wound healing and tumor growth account for the recent attention it has received from the biomedical community.
Topics: Animals; Embryonic and Fetal Development; Extracellular Matrix; Humans; Neoplasms; Osteonectin
PubMed: 10641790
DOI: 10.1016/s1357-2725(99)00090-4 -
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 -
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 -
Pathology, Research and Practice Feb 2024Prostate cancer (PCa) is common malignancy among men worldwide. To date only few molecular markers are available to predict its course and outcome. SPARC is considered...
BACKGROUND
Prostate cancer (PCa) is common malignancy among men worldwide. To date only few molecular markers are available to predict its course and outcome. SPARC is considered to be promising prognostic marker of PCa due to its involvement in various cancer processes.
MATERIALS AND METHODS
study was conducted on PCa surgical primary tumor samples, obtained from 84 patients. Level of SPARC mRNA expression was estimated using RT-qPCR. To identify SPARC protein (osteonectin) in prostate tissue, immunohistochemical analysis was conducted. Bioinformatical analysis was performed on UALCAN and TNMplot resources.
RESULTS
bioinformatical analysis demonstrated that SPARC mRNA levels are decreased in PCa samples, in comparison to normal tissue. In patients with lymph node metastases its levels are 1.26 times higher; p = 4.66E, than in N0 category. Ex vivo study demonstrated that SPARC expression was elevated on both mRNA and protein levels in PCa patients with lymph node metastases (by 2.34 and 1.91, respectively, p < 0.05). We established higher levels of SPARC mRNA and protein in PCa patients with T3 tumors, as well as high Gleason score. Estimation of survival rates demonstrated that PCa patients with a high level of SPARC mRNA and protein have decreased overall 2-year survival.
CONCLUSIONS
SPARC protein was overexpressed on mRNA and protein levels in patients with presence of lymph node metastases and higher Gleason score of tumors. Also, both mRNA and protein upregulation were associated with worse survival rates. The current study has therefore provided further evidence that SPARC is indeed linked to the prognosis and aggressiveness of human PCa.
Topics: Male; Humans; Prognosis; Osteonectin; Lymphatic Metastasis; Prostatic Neoplasms; RNA, Messenger
PubMed: 38199134
DOI: 10.1016/j.prp.2023.155053 -
Applied Immunohistochemistry &...Some studies have correlated secreted protein acidic and rich in cysteine (SPARC) expression with more aggressive behavior in head and neck squamous cell carcinoma...
BACKGROUND
Some studies have correlated secreted protein acidic and rich in cysteine (SPARC) expression with more aggressive behavior in head and neck squamous cell carcinoma (SCC). We investigated the impact of SPARC expression on patient outcomes in a large cohort of SCCs.
MATERIALS AND METHODS
Patients with SCC were identified by searching institutional databases. A tissue microarray of paraffin-embedded tumor specimens was constructed, and SPARC immunohistochemistry was performed. Cellular and stromal SPARC expression were quantitated and correlated with clinicopathologic features.
RESULTS
Of 191 cases, 171 were adequate for SPARC evaluation. A total of 112 (65%) cases showed SPARC tumor cell staining, and 167 (98%) cases showed stromal staining. Increased SPARC stromal expression was correlated with poorer overall survival (OS) [mean (SD) survival, 64.3 (3.25) vs. 42.8 (3.25) mo; P=0.0015] and poorer disease-specific survival (DSS) [mean (SD) survival, 51.1 (1.58) vs. 38.3 (1.832) mo; P=0.0381]. Human papillomavirus-positive status correlated with both stromal and tumor SPARC expression (P=0.0047 and 0.0408, respectively). SPARC staining did not correlate with OS or DSS in multivariate analyses. Among nonchemotherapy patients, SPARC stromal expression was associated with poorer OS and DSS (P=0.0074 and 0.033, respectively). In multivariate analyses, increased stromal SPARC expression was associated with a longer disease-free interval [P=0.0170 (hazard ratio, 1.384)].
CONCLUSIONS
SPARC expression is frequently present in tumoral stroma of head and neck SCCs. In contravention to prior studies, we found that SPARC expression did not correlate with survival overall. This suggests that previously reported associations may not, in fact, exist highlighting the need to meticulously adjust for confounding variables in novel biomarker studies. However, subgroup analysis showed that stromal SPARC expression is associated with better disease-free survival among patients who are not treated with chemotherapy.
Topics: Disease-Free Survival; Head and Neck Neoplasms; Humans; Immunohistochemistry; Osteonectin; Squamous Cell Carcinoma of Head and Neck
PubMed: 35510770
DOI: 10.1097/PAI.0000000000001024 -
Calcified Tissue International Nov 2016Osteonectin, also termed SPARC, is a noncollagenous protein of bone matrix. Since there are controversial results regarding its role during the process of vascular...
Osteonectin, also termed SPARC, is a noncollagenous protein of bone matrix. Since there are controversial results regarding its role during the process of vascular calcification, we investigated osteonectin expression in our in vitro calcification model. Rat vascular smooth muscle cells (VSMCs) were challenged with high phosphate (5 mmol/L Pi) and analyzed quantifying calcium levels, through immunohistochemical studies, and studying gene expression. We detected a peak of osteonectin expression at day 7 in cell treated with high phosphate. The time course of calcium deposition, reflected the expression of osteonectin, resulting extensively present at day 7. On the contrary, the expression of the mitotic marker Ki-67 had a peak at day 4, showing no correlation between osteonectin and cell proliferation. Moreover, 7 days was the time point in which Cbfα1/RUNX-2 had its maximal expression. Furthermore, ascorbic acid increased osteonectin expression, supporting a procalcifying role for this protein. Next we decided to study osteonectin expression ex vivo in fetal, adult not calcified, and adult calcific vessels. Immunohistochemical studies demonstrated a spread and strong reactivity in VSMCs of a 20-week fetus, confirming that osteonectin may have a potential role in regulation of mitosis and in cell differentiation. In adult not calcified arteries, osteonectin was constitutively expressed and its levels increased in atherosclerotic and in calcified plaques, where it could have a regulatory role in the calcification process. Our in vitro and ex vivo data show osteonectin expression during the calcification process and suggest its potential role as procalcifying factor.
Topics: Animals; Muscle, Smooth, Vascular; Osteonectin; Rats; Vascular Calcification
PubMed: 27339669
DOI: 10.1007/s00223-016-0167-x -
International Journal of Oncology May 2016Pancreatic ductal adenocarcinoma (PDAC) is one of the most clinically challenging cancers to manage. An estimated 48,960 people will be diagnosed with pancreatic cancer... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is one of the most clinically challenging cancers to manage. An estimated 48,960 people will be diagnosed with pancreatic cancer in 2015, of that population, 94% are projected to perish within 5 years. These dismal survival rates can be attributed, in part, to an advanced diagnosis occurring in 80% of cases. The heterogeneous and dynamic microenvironment of pancreatic cancer, and the lack of both specific risk factors and efficacious screening tools contribute to the challenge of diagnosing pancreatic cancer in its early stages. These clinical challenges have directed research into the unique characteristics that define PDAC. Recently, there has been an increased focus on the interaction of tumor cells with their microenvironment in the hope of identifying new therapeutic targets. One of the most promising avenues in this new vein of research is targeting protein communication between the cancer cells and the extracellular matrix. The secreted protein acidic and rich in cysteine (SPARC) is one such extracellular matrix protein that has shown potential as a therapeutic target due to its influence on PDAC invasion and metastasis. In this review, we discuss the complex interaction of SPARC with PDAC cells and its potential to guide treatment and eventually improve the survival of patients diagnosed with this devastating disease.
Topics: Carcinoma, Pancreatic Ductal; Early Detection of Cancer; Gene Expression Regulation, Neoplastic; Humans; Osteonectin; Pancreatic Neoplasms; Prognosis; Survival Analysis; Tumor Microenvironment
PubMed: 26983777
DOI: 10.3892/ijo.2016.3417 -
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 -
Connective Tissue Research 2002Osteopontin (OPN) and osteonectin/SPARC (ON/SPARC) are prominent matricellular components of the extracellular matrix of mineralized tissues of bones and teeth in which... (Review)
Review
Osteopontin (OPN) and osteonectin/SPARC (ON/SPARC) are prominent matricellular components of the extracellular matrix of mineralized tissues of bones and teeth in which they can regulate the formation and growth of hydroxyapatite crystals and influence a variety of cell activities. OPN regulates cell responses through several integrin receptors and is also a ligand for the CD44 receptor, through which it acts as a chemoattractant. Although a cell-surface receptor for SPARC has not been identified it can block cell-cell and cell-matrix interactions and inhibit cell migration and chemotaxis. OPN and SPARC also appear to function inside cells. Thus, OPN appears to exist in association with the CD44 receptor inside migratory cells, while intracellular SPARC is associated with axonemal tubulin in ciliated epithelial cells. Analyses of fibroblasts and peritoneal macrophages from OPN-null and CD44-null cells show impaired functionality involving migration and cell fusion required for osteoclast formation, while disruption of SPARC expression leads to developmental defects in Xenopus. To gain further insights into the intracellular functions of OPN and SPARC, we have used the yeast two-hybrid system to identify potential interacting molecules. Using full-length SPARC as bait the carboxy-terminal domain, which contains two EF-hand, high-affinity binding sites, was found to have transcriptional activity, while several novel proteins that interact with the amino-terminal domains of SPARC and full-length OPN have been identified. The identification of OPN and SPARC inside specialized cells introduces a novel concept in cellular regulation by matricellular proteins.
Topics: Animals; Extracellular Matrix Proteins; Extracellular Space; Osteonectin; Osteopontin; Sialoglycoproteins; Tooth; Two-Hybrid System Techniques; Yeasts
PubMed: 12489175
DOI: 10.1080/03008200290001050 -
Annals of Oncology : Official Journal... Nov 2021
Topics: Humans; Lymphoma; Macrophages; Osteonectin
PubMed: 34492312
DOI: 10.1016/j.annonc.2021.08.2152