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Matrix Biology : Journal of the... Mar 2021Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide....
Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide. Several randomized multicenter studies have identified intraocular pressure as the major risk factor for its development, caused by an increased outflow resistance to the aqueous humor within the trabecular meshwork. However, the molecular mechanism for increased outflow resistance in POAG has not been fully established. One of the proposed players is the pro-fibrotic transforming growth factor (TGF)-β2, which is found in higher amounts in the aqueous humor of patients with POAG. In this study we elucidated the role of decorin, a small leucine-rich proteoglycan and known antagonist of TGF-β, in the region of aqueous humor outflow tissue. Utilizing decorin deficient mice, we discovered that decorin modulated TGF-β signaling in the canonical outflow pathways and the lack of decorin in vivo caused an increase in intraocular pressure. Additionally, the Dcn mice showed significant loss of optic nerve axons and morphological changes in the glial lamina, typical features of glaucoma. Moreover, using human trabecular meshwork cells we discovered that soluble decorin attenuated TGF-β2 mediated synthesis and expression of typical downstream target genes including CCN2/CTGF, FN and COL IV. Finally, we found a negative reciprocal regulation of decorin and TGF-β, with a dramatic downregulation of decorin in the canonical outflow pathways of patients with primary open-angle glaucoma. Collectively, our results indicate that decorin plays an important role in the pathogenesis of primary open-angle glaucoma and offers novel perspectives in the treatment of this serious disease.
Topics: Animals; Aqueous Humor; Decorin; Disease Models, Animal; Gene Expression Regulation; Gene Knockout Techniques; Glaucoma, Open-Angle; Humans; Mice; Primary Cell Culture; Signal Transduction; Trabecular Meshwork; Transforming Growth Factor beta
PubMed: 33582236
DOI: 10.1016/j.matbio.2021.02.002 -
The Journal of Clinical Investigation Oct 2022Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis...
Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2-dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS.
Topics: Animals; Bronchiolitis Obliterans; Decorin; Granzymes; Lung Transplantation; Macrophages, Alveolar; Mice; Monocytes; Receptors, CCR2; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta
PubMed: 36189800
DOI: 10.1172/JCI159229 -
Reproduction in Domestic Animals =... Oct 2020In the present study, the concentration of decorin in canine normal and neoplastic mammary gland tissues was examined to understand the potential role of decorin in...
In the present study, the concentration of decorin in canine normal and neoplastic mammary gland tissues was examined to understand the potential role of decorin in development and progression of canine mammary tumours. The homogenates of 48 mammary gland tumours (10 benign and 38 malignant) and 10 samples of normal canine mammary gland tissue were used in the study. The presence and quantification of decorin was examined in the homogenates using Western blot and specific canine ELISA. Western blotting confirmed the presence of decorin both in the normal mammary gland tissues and in the mammary gland tumours. The concentration of decorin was significantly higher (p < .05) in the benign tumours and non-metastatic malignant tumours than in the normal mammary gland. The concentration of decorin was significantly lower (p < .05) in the malignant tumours with metastasis to regional lymph nodes compared with benign tumours and non-metastatic malignant tumours. No significant differences were found in the level of decorin between the benign and the non-metastatic malignant tumours. Both the histological type of malignant tumours and the histological grade did not significantly affect the concentration of decorin. These findings suggest that neoplastic transformation in the canine mammary gland leads to increase in the decorin protein synthesis. The reducing decorin concentration in canine malignant mammary tumours appears to facilitate the metastatic spread of these tumours.
Topics: Adenoma; Animals; Carcinoma; Decorin; Dog Diseases; Dogs; Female; Fibroadenoma; Lymphatic Metastasis; Mammary Glands, Animal; Mammary Neoplasms, Animal; Osteosarcoma
PubMed: 33470009
DOI: 10.1111/rda.13788 -
Matrix Biology : Journal of the... Jan 2022The cervix undergoes rapid and dramatic shifts in collagen and elastic fiber structure to achieve its disparate physiological roles of competence during pregnancy and...
The cervix undergoes rapid and dramatic shifts in collagen and elastic fiber structure to achieve its disparate physiological roles of competence during pregnancy and compliance during birth. An understanding of the structure-function relationships of collagen and elastic fibers to maintain extracellular matrix (ECM) homeostasis requires an understanding of the mechanisms executed by non-structural ECM molecules. Small-leucine rich proteoglycans (SLRPs) play key functions in biology by affecting collagen fibrillogenesis and regulating enzyme and growth factor bioactivities. In the current study, we evaluated collagen and elastic fiber structure-function relationships in mouse cervices using mice with genetic ablation of decorin and/or biglycan genes as representative of Class I SLRPs, and lumican gene representative of Class II SLRP. We identified structural defects in collagen fibril and elastic fiber organization in nonpregnant mice lacking decorin, or biglycan or lumican with variable resolution of defects noted during pregnancy. The severity of collagen and elastic fiber defects was greater in nonpregnant mice lacking both decorin and biglycan and defects were maintained throughout pregnancy. Loss of biglycan alone reduced tissue extensibility in nonpregnant mice while loss of both decorin and biglycan manifested in decreased rupture stretch in late pregnancy. Collagen cross-link density was similar in the Class I SLRP null mice as compared to wild-type nonpregnant and pregnant controls. A broader range in collagen fibril diameter along with an increase in mean fibril spacing was observed in the mutant mice compared to wild-type controls. Collectively, these findings uncover functional redundancy and hierarchical roles of Class I and Class II SLRPs as key regulators of cervical ECM remodeling in pregnancy. These results expand our understating of the critical role SLRPs play to maintain ECM homeostasis in the cervix.
Topics: Animals; Biglycan; Cervix Uteri; Chondroitin Sulfate Proteoglycans; Decorin; Extracellular Matrix Proteins; Female; Fibromodulin; Humans; Lumican; Mice; Pregnancy; Small Leucine-Rich Proteoglycans; Uterine Cervical Neoplasms
PubMed: 34863915
DOI: 10.1016/j.matbio.2021.11.004 -
Methods in Molecular Biology (Clifton,... 2023Proteoglycans (PGs) are non-fibrillar extracellular matrix (ECM) molecules composed by a protein core and glycosaminoglycan (GAG) chains. These molecules are present in...
Proteoglycans (PGs) are non-fibrillar extracellular matrix (ECM) molecules composed by a protein core and glycosaminoglycan (GAG) chains. These molecules are present in all tissues playing essential structural, biomechanical, and biological roles. In addition, PGs can regulate cell behavior due to their versatility and ability to interact with other ECM molecules, growth factors, and cells. The distribution of PGs can be evaluated by histochemical and immunohistochemical methods. Histochemical methods aimed to provide a useful overview of the presence and distribution pattern of certain groups of PGs. In contrast, immunohistochemical procedures aimed the identification of highly specific target molecules. In this chapter we described Alcian Blue, Safranin O, and Toluidine Blue histochemical methods for the screening of PGs in tissue sections. Finally, we describe the immunohistochemical procedures for specific identification of PGs (decorin, biglycan, and versican) in formaldehyde-fixed and paraffin-embedded tissues.
Topics: Alcian Blue; Biglycan; Chondroitin Sulfate Proteoglycans; Decorin; Extracellular Matrix Proteins; Formaldehyde; Glycosaminoglycans; Tolonium Chloride; Versicans
PubMed: 36152244
DOI: 10.1007/978-1-0716-2675-7_7 -
Experimental Eye Research Jun 2021Our earlier decorin (Dcn) gene overexpression studies found that the targeted Dcn gene transfer into the cornea inhibited corneal angiogenesis in vivo using a rabbit...
Our earlier decorin (Dcn) gene overexpression studies found that the targeted Dcn gene transfer into the cornea inhibited corneal angiogenesis in vivo using a rabbit model. In this study, we tested the hypothesis that anti-angiogenic effects of decorin in the cornea are mediated by alterations in a normal physiologic balance of pro- and anti-angiogenic factors using decorin deficient (Dcn) and wild type (Dcn) mice. Corneal neovascularization (CNV) in Dcn and Dcn mice was produced with a standard chemical injury technique. The clinical progression of CNV in mice was monitored with stereo- and slit-lamp microscopes, and histopathological hematoxylin and eosin (H&E) staining. Protein and mRNA expression of pro- and anti-angiogenic factors in the cornea were evaluated using immunofluorescence and quantitative real-time PCR, respectively. Slit-lamp clinical eye examinations revealed significantly more CNV in Dcn mice than the Dcn mice post-injury (p < 0.05) and AAV5-Dcn gene therapy significantly reduced CNV in Dcn mice compered to no AAV5-Dcn gene therapy controls (p < 0.001). H&E-stained corneal sections exhibited morphology with several neovessels in injured corneas of the Dcn mice than the Dcn mice. Immunofluorescence of corneal sections displayed significantly higher expression of α-smooth muscle actin (α-SMA) and endoglin proteins in Dcn mice than Dcn mice (p < 0.05). Quantitative real-time PCR found significantly increased mRNA levels of pro-angiogenic factors endoglin (2.53-fold; p < 0.05), Vegf (2.47-fold; p < 0.05), and Pecam (2.14-fold; p < 0.05) and anti-angiogenic factor Vegfr2 (1.56-fold; p < 0.05) in the normal cornea of the Dcn mice than the Dcn mice. Furthermore, neovascularized Dcn mice corneas showed greater increase in mRNA expression of pro-angiogenic factors endoglin (4.58-fold; p < 0.0001), Vegf (4.16-fold; p < 0.0001), and Pdgf (2.15-fold; p < 0.0001) and reduced expression of anti-angiogenic factors Ang2 (0.12-fold; p < 0.05), Timp1 (0.22-fold; p < 0.05), and Vegfr2 (0.67-fold; p > 0.05) compared to neovascularized Dcn mice corneas. These gene deficience studies carried with transgenic Dcn mice revealed decorin's role in influencing a physiologic balance between pro-and anti-angiogenic factors in the normal and injured cornea. We infer that the functional deletion of Dcn promotes irregular corneal repair and aggravates CNV.
Topics: Actins; Animals; Corneal Neovascularization; Decorin; Endoglin; Female; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Platelet Endothelial Cell Adhesion Molecule-1; RNA, Messenger; Real-Time Polymerase Chain Reaction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 33940009
DOI: 10.1016/j.exer.2021.108610 -
European Journal of Endocrinology Feb 2018Growth hormone (GH) stimulates connective tissue and muscle growth, an effect that is potentiated by testosterone. Decorin, a myokine and a connective tissue protein,... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Growth hormone (GH) stimulates connective tissue and muscle growth, an effect that is potentiated by testosterone. Decorin, a myokine and a connective tissue protein, stimulates connective tissue accretion and muscle hypertrophy. Whether GH and testosterone regulate decorin in humans is not known.
OBJECTIVE
To determine whether decorin is stimulated by GH and testosterone.
DESIGN
Randomized, placebo-controlled, double-blind study.
PARTICIPANTS AND INTERVENTION
96 recreationally trained athletes (63 men, 33 women) received 8 weeks of treatment followed by a 6-week washout period. Men received placebo, GH (2 mg/day), testosterone (250 mg/week) or combination. Women received either placebo or GH (2 mg/day).
MAIN OUTCOME MEASURE
Serum decorin concentration.
RESULTS
GH treatment significantly increased mean serum decorin concentration by 12.7 ± 4.2%; < 0.01. There was a gender difference in the decorin response to GH, with greater increase in men than in women (∆ 16.5 ± 5.3%; < 0.05 compared to ∆ 9.4 ± 6.5%; = 0.16). Testosterone did not significantly change serum decorin. Combined GH and testosterone treatment increased mean decorin concentration by 19.5 ± 3.7% ( < 0.05), a change not significantly different from GH alone.
CONCLUSION
GH significantly increases circulating decorin, an effect greater in men than in women. Decorin is not affected by testosterone. We conclude that GH positively regulates decorin in humans in a gender-dimorphic manner.
Topics: Adult; Androgens; Athletes; Decorin; Double-Blind Method; Female; Human Growth Hormone; Humans; Male; Sex Factors; Testosterone; Young Adult
PubMed: 29138241
DOI: 10.1530/EJE-17-0844 -
Current Opinion in Rheumatology Nov 2016This article updates on the concept that muscle-derived cytokines (myokines) play important roles in muscle health and disease. (Review)
Review
PURPOSE OF REVIEW
This article updates on the concept that muscle-derived cytokines (myokines) play important roles in muscle health and disease.
RECENT FINDINGS
Interleukin-6 (IL-6) is released from normal skeletal muscle in response to exercise, mediating both anti-inflammatory responses and metabolic adaptations, actions contradictory to the prevailing view that IL-6 is a proinflammatory cytokine that is inducing and propagating disease. The anti-inflammatory effects of IL-6 result from its trans-membrane signalling capability, via membrane-bound receptors, whereas its proinflammatory effects result instead from signalling via the soluble IL-6 receptor and gp130. IL-15 is elevated following exercise, promoting muscle fibre hypertrophy in some circumstances, while inducing fibre apoptosis in others. This functional divergence appears because of variations in expression of IL-15 receptor isoforms. Decorin, a recently described myokine, is also elevated following exercise in normal muscle, and promotes muscle fibre hypertrophy by competitively binding to, and thus inhibiting, myostatin, a negative regulator of muscle protein synthesis. Exercise-induced myostatin downregulation thus promotes muscle fibre growth, prompting recent trials of a biological myostatin inhibitor in inclusion body myositis.
SUMMARY
Myokines appear to exert diverse beneficial effects, though their mechanistic roles in myositis and other myopathologies remain poorly understood.
Topics: Cytokines; Decorin; Exercise; Humans; Interleukin-6; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Diseases; Myostatin; Receptors, Interleukin-6; Signal Transduction
PubMed: 27548653
DOI: 10.1097/BOR.0000000000000337 -
The Indian Journal of Medical Research Apr 2021Decorin is a proteoglycan that plays a role in the binding of collagen and has an important role in the pathogenesis of osteoarthritis (OA). This study was aimed to...
BACKGROUND & OBJECTIVES
Decorin is a proteoglycan that plays a role in the binding of collagen and has an important role in the pathogenesis of osteoarthritis (OA). This study was aimed to determine serum and synovial fluid decorin levels in patients with knee OA and to investigate whether these levels were associated with OA and the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score.
METHODS
In this prospective study 88 participants were included (44 knee OA and 44 with other knee joint diseases) in the study and control groups. Knee function was assessed using the WOMAC score. The serum and synovial fluid decorin levels were analyzed using a human decorin ELISA. Binary logistic regression with a single and multi-categorical predictor was used to determine the possible risk factors for OA.
RESULTS
The serum decorin levels were significantly higher in the OA group than the control group (P<0.002).s The synovial fluid decorin levels were not significantly different between OA and control groups. WOMAC score [odds ratio (OR)=1.073, 95% confidence interval (CI): 1.032-1.116, P<0.001] and high serum decorin levels (OR=1.114, 95%CI: 1.030-1.205, P=0.007) were found to be significant in the determination of OA. Serum decorin levels were positively correlated with the WOMAC score in OA.
INTERPRETATION & CONCLUSIONS
An increased serum decorin levels may be indicative of changes in extracellular matrix structure. The positive correlation between serum decorin level and WOMAC score supports this result. Increased serum decorin levels and WOMAC score were found to be risk factors associated with OA. However, the decorin level in the joint fluid was not associated with OA.
Topics: Decorin; Humans; Osteoarthritis, Knee; Prospective Studies; Severity of Illness Index; Synovial Fluid
PubMed: 34380791
DOI: 10.4103/ijmr.IJMR_2020_18 -
Frontiers in Oncology 2021Decorin exhibits inhibitory effects in tumorigenesis in various types of cancers. The clinical characteristics of 42 patients with GBM were reviewed and analyzed....
Decorin exhibits inhibitory effects in tumorigenesis in various types of cancers. The clinical characteristics of 42 patients with GBM were reviewed and analyzed. Lentiviral constructs for decorin overexpression and shRNA-mediated silencing were established for U87MG cells and T98G cells, respectively. The expressions of EMT- and autophagy-associated markers were detected in GBM cell lines. The migration and invasion of the glioma cells were assayed to reflect the malignant behavior of GBM. A mouse xenograft model was used to verify the effect of decorin on autophagy . Reduced expression of decorin in glioma tissues was associated with a poor survival of the patients. Decorin overexpression suppressed cell migration, invasion and attenuated EMT phenotype in glioma cell lines. Further study indicated that decorin inhibited EMT phenotype through the induction of autophagy. The mechanisms include inhibiting the activation of c-Met/Akt/mTOR signaling and regulating the expressions of mesenchymal markers including Slug, vimentin and Twist, and epithelial marker E-cadherin. In addition, decorin overexpression in a mice model can also suppress the GBM invasion and EMT phenotype. In conclusion, decorin suppresses invasion and EMT phenotype of glioma by inducing autophagy c-Met/Akt/mTOR axis.
PubMed: 34386415
DOI: 10.3389/fonc.2021.659353