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Journal of Biomechanical Engineering Jun 2022Cervical remodeling is critical for a healthy pregnancy. The proper regulation of extracellular matrix (ECM) turnover leads to remodeling throughout gestation,...
Cervical remodeling is critical for a healthy pregnancy. The proper regulation of extracellular matrix (ECM) turnover leads to remodeling throughout gestation, transforming the tissue from a stiff material to a compliant, extensible, viscoelastic tissue prepared for delivery. Small leucine-rich proteoglycans (SLRPs) regulate structural fiber assembly in the cervical ECM and overall tissue material properties. To quantify the SLRPs' mechanical role in the cervix, whole cervix specimens from nonpregnant and late pregnant knockout mice of SLRPs, decorin and biglycan, were subjected to cyclic load-unload, ramp-hold, and load-to-failure mechanical tests. Further, a fiber composite material model, accounting for collagen fiber bundle waviness, was developed to describe the cervix's three-dimensional large deformation equilibrium behavior. In nonpregnant tissue, SLRP knockout cervices have the same equilibrium material properties as wild-type tissue. In contrast, the load-to-failure and ramp-hold tests reveal SLRPs impact rupture and time-dependent relaxation behavior. Loss of decorin in nonpregnant (NP) cervices results in inferior rupture properties. After extensive remodeling, cervical strength is similar between all genotypes, but the SLRP-deficient tissue has a diminished ability to dissipate stress during a ramp-hold. In mice with a combined loss of decorin and biglycan, the pregnant cervix loses its extensibility, compliance, and viscoelasticity. These results suggest that decorin and biglycan are necessary for crucial extensibility and viscoelastic material properties of a healthy, remodeled pregnant cervix.
Topics: Animals; Biglycan; Cervix Uteri; Decorin; Extracellular Matrix; Extracellular Matrix Proteins; Female; Mice; Mice, Knockout; Pregnancy
PubMed: 35348624
DOI: 10.1115/1.4054199 -
International Journal of Molecular... Mar 2017In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5...
In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 through selective utilization of Toll-like receptors (TLRs) and their adaptor molecules. However, the respective downstream signaling events resulting in biglycan-induced CCL2 and CCL5 production have not yet been defined. Here, we show that biglycan stimulates the production and activation of sphingosine kinase 1 (SphK1) in a TLR4- and Toll/interleukin (IL)-1R domain-containing adaptor inducing interferon (IFN)-β (TRIF)-dependent manner in murine primary macrophages. We provide genetic and pharmacological proof that SphK1 is a crucial downstream mediator of biglycan-triggered CCL2 and CCL5 mRNA and protein expression. This is selectively driven by biglycan/SphK1-dependent phosphorylation of the nuclear factor NF-κB p65 subunit, extracellular signal-regulated kinase (Erk)1/2 and p38 mitogen-activated protein kinases. Importantly, in vivo overexpression of soluble biglycan causes Sphk1-dependent enhancement of renal CCL2 and CCL5 and macrophage recruitment into the kidney. Our findings describe the crosstalk between biglycan- and SphK1-driven extracellular matrix- and lipid-signaling. Thus, SphK1 may represent a new target for therapeutic intervention in biglycan-evoked inflammatory conditions.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Biglycan; Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Extracellular Matrix; HEK293 Cells; Humans; MAP Kinase Signaling System; Macrophages; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphotransferases (Alcohol Group Acceptor); Toll-Like Receptor 4; Transcription Factor RelA; p38 Mitogen-Activated Protein Kinases
PubMed: 28282921
DOI: 10.3390/ijms18030595 -
International Journal of Molecular... Apr 2023variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia...
variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in were implicated in myopathies. Here, we present one patient with a known and six patients with novel missense variants, further characterizing the molecular landscape of this heterogenous neurological disorder. A total of seven patients were genotyped and phenotyped. Skeletal muscle biopsies were analyzed by histology, electron microscopy, and protein profiling to define pathological hallmarks and pathogenicity markers with consecutive validation using fluorescence microscopy. Clinical and MRI-features revealed a typical pattern of distal paresis of the lower extremities as characteristic features of a -associated disorder. Histological evaluation showed myopathic features of varying severity including fiber size variation, lipofibromatosis, and fiber splittings. Proteomic analysis with subsequent fluorescence analysis revealed an altered abundance and localization of thrombospondin-4 and biglycan. Our combined clinical, histopathological, and proteomic approaches provide new insights into the pathophysiology of -associated disorders, confirming a primary muscle cell vulnerability. In this context, biglycan and thrombospondin-4 have been identified, may serve as tissue pathogenicity markers, and might be linked to perturbed protein secretion based on an impaired vesicular transportation.
Topics: Humans; Biglycan; Microtubule-Associated Proteins; Proteomics; Muscular Atrophy, Spinal; Mutation; Muscle, Skeletal
PubMed: 37047781
DOI: 10.3390/ijms24076808 -
Matrix Biology : Journal of the... Dec 2017The small leucine-rich proteoglycans (SLRPs), decorin and biglycan, are key regulators of collagen fibril and matrix assembly. The goal of this work was to elucidate the...
The small leucine-rich proteoglycans (SLRPs), decorin and biglycan, are key regulators of collagen fibril and matrix assembly. The goal of this work was to elucidate the roles of decorin and biglycan in tendon homeostasis. Our central hypothesis is that decorin and biglycan expression in the mature tendon would be critical for the maintenance of the structural and mechanical properties of healthy tendons. Defining the function(s) of these SLRPs in tendon homeostasis requires that effects in the mature tendon be isolated from their influence on development. Thus, we generated an inducible knockout mouse model that permits genetic ablation of decorin and biglycan expression in the mature tendon, while maintaining normal expression during development. Decorin and biglycan expression were knocked out in the mature patellar tendon with the subsequent turnover of endogenous SLRPs deposited prior to induction. The acute absence of SLRP expression was associated with changes in fibril structure with a general shift to larger diameter fibrils in the compound knockout tendons, together with fibril diameter heterogeneity. In addition, tendon mechanical properties were altered. Compared to wild-type controls, acute ablation of both genes resulted in failure of the tendon at lower loads, decreased stiffness, a trend towards decreased dynamic modulus, as well as a significant increase in percent relaxation and tissue viscosity. Collagen fiber realignment was also increased with a delayed and slower in response to load in the absence of expression. These structural and functional changes in response to an acute loss of decorin and biglycan expression in the mature tendon demonstrate a significant role for these SLRPs in adult tendon homeostasis.
Topics: Animals; Biglycan; Biomechanical Phenomena; Collagen; Decorin; Gene Knockout Techniques; Homeostasis; Mice; Patellar Ligament
PubMed: 28882761
DOI: 10.1016/j.matbio.2017.08.004 -
Scientific Reports Mar 2021Hypertrophy of the ligamentum flavum (LF) is a major cause of lumbar spinal stenosis (LSS), and the pathology involves disruption of elastic fibers, fibrosis with...
Hypertrophy of the ligamentum flavum (LF) is a major cause of lumbar spinal stenosis (LSS), and the pathology involves disruption of elastic fibers, fibrosis with increased cellularity and collagens, and/or calcification. Previous studies have implicated the increased expression of the proteoglycan family in hypertrophied LF. Furthermore, the gene expression profile in a rabbit experimental model of LF hypertrophy revealed that biglycan (BGN) is upregulated in hypertrophied LF by mechanical stress. However, the expression and function of BGN in human LF has not been well elucidated. To investigate the involvement of BGN in the pathomechanism of human ligamentum hypertrophy, first we confirmed increased expression of BGN by immunohistochemistry in the extracellular matrix of hypertrophied LF of LSS patients compared to LF without hypertrophy. Experiments using primary cell cultures revealed that BGN promoted cell proliferation. Furthermore, BGN induces changes in cell morphology and promotes myofibroblastic differentiation and cell migration. These effects are observed for both cells from hypertrophied and non-hypertrophied LF. The present study revealed hyper-expression of BGN in hypertrophied LF and function of increased proteoglycan in LF cells. BGN may play a crucial role in the pathophysiology of LF hypertrophy through cell proliferation, myofibroblastic differentiation, and cell migration.
Topics: Adult; Aged; Animals; Biglycan; Elastic Tissue; Extracellular Matrix; Female; Fibrosis; Humans; Hypertrophy; Ligamentum Flavum; Lumbar Vertebrae; Male; Middle Aged; Rabbits; Spinal Stenosis; Stress, Mechanical
PubMed: 33649499
DOI: 10.1038/s41598-021-84363-x -
The Journal of Infectious Diseases Jun 2019Borrelia burgdorferi sensu lato spirochetes (Borrelia) causing Lyme borreliosis are able to disseminate from the initial entry site to distant organs in the host....
BACKGROUND
Borrelia burgdorferi sensu lato spirochetes (Borrelia) causing Lyme borreliosis are able to disseminate from the initial entry site to distant organs in the host. Outer-surface adhesins are crucial in the bacterial dissemination and adhesion to various tissues. Two well-characterized Borrelia adhesins, decorin-binding proteins A and B, have been shown to bind to 2 host receptors, decorin and biglycan. However, the role of biglycan in Borrelia infection has not been characterized in vivo.
METHODS
We infected biglycan knockout (KO) and wild-type (WT) C3H mice with strains representing 3 Borrelia genospecies, Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii. The infection was monitored by measuring joint swelling, Borrelia culture, polymerase chain reaction analysis, and serologic analysis. The host immune responses were analyzed by histological scoring of the inflammation in tissues and by cytokine profiling.
RESULTS
B. burgdorferi sensu stricto and B. garinii established long-term infection in mice of both genotypes, while B. afzelii failed to disseminate in KO mice. Further, the B. burgdorferi sensu stricto-infected KO mice had persistent inflammation in the joints.
CONCLUSIONS
The dissemination and tissue colonization of Borrelia and the inflammatory response of the host differ in a mouse biglycan expression- and Borrelia genospecies-dependent manner.
Topics: Adhesins, Bacterial; Animals; Biglycan; Borrelia burgdorferi; Decorin; Female; Lyme Disease; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Polymerase Chain Reaction
PubMed: 30698707
DOI: 10.1093/infdis/jiz050 -
Oncoimmunology 2022The extracellular matrix component biglycan (BGN) plays an essential role in various physiological and pathophysiological processes. A deficient BGN expression...
The extracellular matrix component biglycan (BGN) plays an essential role in various physiological and pathophysiological processes. A deficient BGN expression associated with reduced immunogenicity was found in HER-2/neu-overexpressing cells. To determine whether BGN is suppressed by oncogene-driven regulatory networks, the expression and function of BGN was analyzed in murine and human BGN/BGN K-RAS-transformed model systems as well as in different patients' datasets of colorectal carcinoma (CRC) lesions. K-RAS-mutated CRC tissues expressed low BGN mRNA and protein levels when compared to normal colon epithelial cells, which was associated with a reduced patients' survival. Transfection of BGN in murine and human BGN K-RAS-expressing cells resulted in a reduced growth and migration of BGN vs BGN K-RAS cells. In addition, increased MHC class I surface antigens as a consequence of an enhanced antigen processing machinery component expression was found upon restoration of BGN, which was confirmed by RNA-sequencing of BGN vs. BGN K-RAS models. Furthermore, a reduced tumor formation of BGN versus BGN K-RAS-transformed fibroblasts associated with an enhanced MHC class I expression and an increased frequency of tumor-infiltrating lymphocytes in tumor lesions was found. Our data provide for the first time an inverse link between BGN and K-RAS expression in murine and human K-RAS-overexpressing models and CRC lesions associated with altered growth properties, reduced immunogenicity and worse patients' outcome. Therefore, reversion of BGN might be a novel therapeutic option for K-RAS-associated malignancies.
Topics: Animals; Biglycan; Colorectal Neoplasms; Fibroblasts; Histocompatibility Antigens Class I; Humans; Mice; RNA, Messenger; Transfection
PubMed: 35529675
DOI: 10.1080/2162402X.2022.2069214 -
The International Journal of... Sep 2014Chronic renal inflammation is often associated with a progressive accumulation of various extracellular matrix constituents, including several members of the small... (Review)
Review
Chronic renal inflammation is often associated with a progressive accumulation of various extracellular matrix constituents, including several members of the small leucine-rich proteoglycan (SLRP) gene family. It is becoming increasingly evident that the matrix-unbound SLRPs strongly regulate the progression of inflammation and fibrosis. Soluble SLRPs are generated either via partial proteolytic processing of collagenous matrices or by de novo synthesis evoked by stress or injury. Liberated SLRPs can then bind to and activate Toll-like receptors, thus modulating downstream inflammatory signaling. Preclinical animal models and human studies have recently identified soluble biglycan as a key initiator and regulator of various inflammatory renal diseases. Biglycan, generated by activated macrophages, can enter the circulation and its elevated levels in plasma and renal parenchyma correlate with unfavorable renal function and outcome. In this review, we will focus on the critical role of soluble biglycan in inflammatory signaling in various renal disorders. Moreover, we will provide new data implicating proinflammatory effects of soluble decorin in unilateral ureteral obstruction. Finally, we will critically evaluate the potential application of soluble biglycan vis-à-vis other SLRPs (decorin, lumican and fibromodulin) as a promising target and novel biomarker of inflammatory renal diseases.
Topics: Animals; Biglycan; Biomarkers; Humans; Inflammation; Kidney Diseases
PubMed: 25091702
DOI: 10.1016/j.biocel.2014.07.020 -
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 -
Journal of Cellular and Molecular... Feb 2011Small leucine-rich proteoglycans (SLRPs), such as decorin and biglycan, regulate the assembly and turnover of collagenous matrix. The aim of the study was to analyse the...
Small leucine-rich proteoglycans (SLRPs), such as decorin and biglycan, regulate the assembly and turnover of collagenous matrix. The aim of the study was to analyse the effect of chronic rosuvastatin treatment on decorin, biglycan and the collagen matrix in ApoE-deficient mice. Twenty-week-old male ApoE-deficient mice received normal chow or 20 mg rosuvastatin/kg × day for 32 weeks. Subsequently, matrix composition was analysed by histochemistry and immunostaining at the aortic root and in innominate arteries of ApoE deficient mice as well as in human carotid endarterectomy specimens. Immunoblotting of proteoglycans was performed from aortic extracts of ApoE-deficient mice. Immunohistochemistry and immunoblotting revealed strongly increased decorin and biglycan deposition in atherosclerotic plaques at the aortic root and in innominate arteries. In contrast, versican and perlecan expression was not changed by rosuvastatin. Furthermore, matrix metalloproteinase 2 and gelatinolytic activity were decreased in response to rosuvastatin and a condensed collagen-rich matrix was formed. In carotid endarterectomy specimens of statin-treated patients increased decorin and biglycan accumulation was detected as well. Drug treatment did not change low-density lipoprotein (LDL) plasma levels in ApoE-deficient mice and did not significantly affect lipid retention at the aortic root level as demonstrated by oil-red O staining and immunohistochemistry of LDL. Long-term treatment with rosuvastatin caused pronounced remodelling of atherosclerotic plaque matrix characterized specifically by enrichment with SLRPs and formation of a condensed collagen matrix. Therefore, decorin and biglycan might represent novel targets of statin treatment that contribute to a stable plaque phenotype.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Biglycan; Cell Line; Collagen; Decorin; Endarterectomy, Carotid; Extracellular Matrix Proteins; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leucine; Lipoproteins, LDL; Male; Mice; Mice, Knockout; Plaque, Atherosclerotic; Proteoglycans; Pyrimidines; Rosuvastatin Calcium; Sulfonamides
PubMed: 20015203
DOI: 10.1111/j.1582-4934.2009.00986.x