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International Journal of Molecular... Sep 2021Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural-functional integrity of the placenta and fetal membranes, and their... (Review)
Review
Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural-functional integrity of the placenta and fetal membranes, and their alterations can result in several pregnancy-associated diseases. In this review, we briefly discuss normal placental structure and functions, define and classify SLRPs, and then focus on two SLRPs, decorin (DCN) and biglycan (BGN). We discuss the consequences of deletions/mutations of DCN and BGN. We then summarize DCN and BGN expression in the pregnant uterus, myometrium, decidua, placenta, and fetal membranes. Actions of these SLRPs as ligands are then discussed in the context of multiple binding partners in the extracellular matrix and cell surface (receptors), as well as their alterations in pathological pregnancies, such as preeclampsia, fetal growth restriction, and preterm premature rupture of membranes. Lastly, we raise some unanswered questions as food for thought.
Topics: Animals; Biglycan; Decorin; Female; Fetal Growth Retardation; Gene Expression Regulation; Humans; Mutation; Placenta; Pre-Eclampsia; Pregnancy
PubMed: 34638928
DOI: 10.3390/ijms221910584 -
Osteoarthritis and Cartilage Aug 2021To delineate the activities of decorin and biglycan in the progression of post-traumatic osteoarthritis (PTOA).
OBJECTIVE
To delineate the activities of decorin and biglycan in the progression of post-traumatic osteoarthritis (PTOA).
DESIGN
Three-month-old inducible biglycan (Bgn) and decorin/biglycan compound (Dcn/Bgn) knockout mice were subjected to the destabilization of the medial meniscus (DMM) surgery to induce PTOA. The OA phenotype was evaluated by assessing joint structure and sulfated glycosaminoglycan (sGAG) staining via histology, surface collagen fibril nanostructure and calcium content via scanning electron microscopy, tissue modulus via atomic force microscopy-nanoindentation, as well as subchondral bone structure and meniscus ossification via micro-computed tomography. Outcomes were compared with previous findings in the inducible decorin (Dcn) knockout mice.
RESULTS
In the DMM model, Bgn mice developed similar degree of OA as the control (0.44 [-0.18 1.05] difference in modified Mankin score), different from the more severe OA phenotype observed in Dcn mice (1.38 [0.91 1.85] difference). Dcn/Bgn mice exhibited similar histological OA phenotype as Dcn mice (1.51 [0.97 2.04] difference vs control), including aggravated loss of sGAGs, salient surface fibrillation and formation of osteophyte. Meanwhile, Dcn/Bgn mice showed further cartilage thinning than Dcn mice, resulting in the exposure of underlying calcified tissues and aberrantly high surface modulus. Bgn and Dcn/Bgn mice developed altered subchondral trabecular bone structure in both Sham and DMM groups, while Dcn and control mice did not.
CONCLUSION
In PTOA, decorin plays a more crucial role than biglycan in regulating cartilage degeneration, while biglycan is more important in regulating subchondral bone structure. The two have distinct activities and modest synergy in the pathogenesis of PTOA.
Topics: Animals; Biglycan; Cancellous Bone; Cartilage, Articular; Decorin; Disease Models, Animal; Disease Progression; Menisci, Tibial; Mice, Knockout; Ossification, Heterotopic; Osteoarthritis; Osteophyte; Tibial Meniscus Injuries; Mice
PubMed: 33915295
DOI: 10.1016/j.joca.2021.03.019 -
Reproductive Sciences (Thousand Oaks,... Jan 2021Preterm birth is a leading cause of infant morbidity and mortality. Decorin and biglycan are proteoglycans that play key roles in maintaining the connective tissue...
Preterm birth is a leading cause of infant morbidity and mortality. Decorin and biglycan are proteoglycans that play key roles in maintaining the connective tissue matrix and tensile strength of human fetal membranes and have been previously linked to PPROM. Extracellular matrix proteins, such as matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), TIMP metallopeptidase inhibitor 1 (TIMP-1), TIMP metallopeptidase inhibitor 2 (TIMP-2), and collagen VI (COL-6), have also been linked to PPROM and may have utility in a serum-based screening model for this condition. To define the natural course of serum decorin and biglycan expression throughout the duration of healthy pregnancy, to explore patterns of serum decorin and biglycan expression in serum of asymptomatic women who go on to develop spontaneous preterm labor, and to investigate the potential role for matrix metalloproteinases, their inhibitors, and collagen VI in a serum-based screening model to predict PPROM. Serum decorin level decreases less than 1% per week, and serum biglycan decreases by 2.9% per week over the duration of healthy pregnancy. Serum decorin and biglycan concentrations do not differ in spontaneous preterm labor cases compared with those in controls. Mean concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, and COL-6 do not differ in PPROM cases compared with those in controls. We have demonstrated that serum decorin and biglycan concentrations remain stable throughout the duration of normal pregnancy and are not early indicators of preterm labor, while common MMPs, TIMPs, and collagen VI are not early indicators of PPROM.
Topics: Biglycan; Biomarkers; Collagen Type VI; Decorin; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Fetal Membranes, Premature Rupture; Humans; Matrix Metalloproteinases; Predictive Value of Tests; Pregnancy; Premature Birth; Retrospective Studies; Tissue Inhibitor of Metalloproteinases
PubMed: 32804350
DOI: 10.1007/s43032-020-00251-1 -
Matrix Biology : Journal of the... Aug 2018The extracellular matrix (ECM) plays key roles in normal and diseased skeletal and cardiac muscle. In healthy muscle the ECM is essential for transmitting contractile... (Review)
Review
The extracellular matrix (ECM) plays key roles in normal and diseased skeletal and cardiac muscle. In healthy muscle the ECM is essential for transmitting contractile force, maintaining myofiber integrity and orchestrating cellular signaling. Duchenne Muscular Dystrophy (DMD) is caused by loss of dystrophin, a cytosolic protein that anchors a transmembrane complex and serves as a vital link between the actin cytoskeleton and the basal lamina. Loss of dystrophin leads to membrane fragility and impaired signaling, resulting in myofiber death and cycles of inflammation and regeneration. Fibrosis is also a cardinal feature of DMD. In this review, we will focus on two cases where understanding the normal function and regulation of ECM in muscle has led to the discovery of candidate therapeutics for DMD. Biglycan is a small leucine rich repeat ECM protein present as two glycoforms in muscle that have dramatically different functions. One widely expressed form is biglycan proteoglycan (PG) that bears two chondroitin sulfate GAG chains (typically chondroitin sulfate) and two N-linked carbohydrates. The second glycoform, referred to as 'NG' (non-glycanated) biglycan, lacks the GAG side chains. NG, but not PG biglycan recruits utrophin, an autosomal paralog of dystrophin, and an NOS-containing signaling complex to the muscle cell membrane. Recombinant NG biglycan can be systemically delivered to dystrophic mice where it upregulates utrophin at the membrane and improves muscle health and function. An optimized version of NG biglycan, 'TVN-102', is under development as a candidate therapeutic for DMD. A second matrix-embedded protein being evaluated for therapeutic potential is latent TGFβ binding protein 4 (LTBP4). Identified in a genomic screen for modifiers of muscular dystrophy, LTBP4 binds both TGFβ and myostatin. Genetic studies identified the hinge region of LTBP4 as linked to TGFβ release and contributing to the "hyper-TGFβ" signaling state that promotes fibrosis in muscular dystrophy. This hinge region can be stabilized by antibodies directed towards this domain. Stabilizing the hinge region of LTBP4 is expected to reduce latent TGFβ release and thus reduce fibrosis.
Topics: Animals; Biglycan; Cell Membrane; Clinical Trials as Topic; Extracellular Matrix; Genetic Therapy; Humans; Latent TGF-beta Binding Proteins; Muscle, Skeletal; Muscular Dystrophy, Duchenne
PubMed: 29481844
DOI: 10.1016/j.matbio.2018.02.016 -
The FEBS Journal Jan 2017Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and... (Review)
Review
Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview, we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which soluble extracellular matrix constituents affect the microenvironment associated with inflammatory and neoplastic diseases.
Topics: Autophagy; Biglycan; Cytokines; Decorin; Endothelial Cells; ErbB Receptors; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 27860287
DOI: 10.1111/febs.13963 -
Frontiers in Oncology 2023Exit of quiescent disseminated cancer cells from dormancy is thought to be responsible for metastatic relapse and a better understanding of dormancy could pave the way...
Exit of quiescent disseminated cancer cells from dormancy is thought to be responsible for metastatic relapse and a better understanding of dormancy could pave the way for novel therapeutic approaches. We used an model of triple negative breast cancer brain metastasis to identify differences in transcriptional profiles between dormant and proliferating cancer cells in the brain. gene, encoding a small proteoglycan biglycan, was strongly upregulated in dormant cancer cells . expression was significantly downregulated in patient brain metastases as compared to the matched primary breast tumors and overexpression in cancer cells inhibited their growth and . Dormant cancer cells were further characterized by a reduced expression of glycolysis genes , and inhibition of glycolysis resulted in a reversible growth arrest reminiscent of dormancy. Our study identified mechanisms that could be targeted to induce/maintain cancer dormancy and thereby prevent metastatic relapse.
PubMed: 37456245
DOI: 10.3389/fonc.2023.1191980 -
Matrix Biology Plus Feb 2022Tendon is a vital musculoskeletal tissue that is prone to degeneration. Proper tendon maintenance requires complex interactions between extracellular matrix components...
Tendon is a vital musculoskeletal tissue that is prone to degeneration. Proper tendon maintenance requires complex interactions between extracellular matrix components that remain poorly understood. Collagen VI and biglycan are two matrix molecules that localize pericellularly within tendon and are critical regulators of tissue properties. While evidence suggests that collagen VI and biglycan interact within the tendon matrix, the relationship between the two molecules and its impact on tendon function remains unknown. We sought to elucidate potential coordinate roles of collagen VI and biglycan within tendon by defining tendon properties in knockout models of collagen VI, biglycan, or both molecules. We first demonstrated co-expression and co-localization of collagen VI and biglycan within the healing tendon, providing further evidence of cooperation between the two molecules during nascent tendon matrix formation. Deficiency in collagen VI and/or biglycan led to significant reductions in collagen fibril size and tendon mechanical properties. However, collagen VI-null tendons displayed larger reductions in fibril size and mechanics than seen in biglycan-null tendons. Interestingly, knockout of both molecules resulted in similar properties to collagen VI knockout alone. These results indicate distinct and non-additive roles for collagen VI and biglycan within tendon. This work provides better understanding of regulatory interactions between two critical tendon matrix molecules.
PubMed: 35036900
DOI: 10.1016/j.mbplus.2021.100099 -
The Journal of Histochemistry and... Dec 2012Research over the past few years has provided fascinating results indicating that biglycan, besides being a ubiquitous structural component of the extracellular matrix... (Review)
Review
Research over the past few years has provided fascinating results indicating that biglycan, besides being a ubiquitous structural component of the extracellular matrix (ECM), may act as a signaling molecule. Proteolytically released from the ECM, biglycan acts as a danger signal signifying tissue stress or injury. As a ligand of innate immunity receptors and activator of the inflammasome, biglycan stimulates multifunctional proinflammatory signaling linking the innate to the adaptive immune response. By clustering several types of receptors on the cell surface and orchestrating their downstream signaling events, biglycan is capable to autonomously trigger sterile inflammation and to potentiate the inflammatory response to microbial invasion. Besides operating in a broad biological context, biglycan also displays tissue-specific affinities to certain receptors and structural components, thereby playing a crucial role in bone formation, muscle integrity, and synapse stability at the neuromuscular junction. This review attempts to provide a concise summary of recent data regarding the involvement of biglycan in the regulation of inflammation and the musculoskeletal system, pointing out both a signaling and a structural role for this proteoglycan. The potential of biglycan as a novel therapeutic target or agent for the treatment of inflammatory diseases and skeletal muscular dystrophies is also addressed.
Topics: Adaptive Immunity; Animals; Biglycan; Carrier Proteins; Extracellular Matrix; Humans; Immunity, Innate; Inflammation; Interleukin-1beta; Muscular Dystrophies; NLR Family, Pyrin Domain-Containing 3 Protein; Osteogenesis; Signal Transduction; Toll-Like Receptors
PubMed: 22821552
DOI: 10.1369/0022155412456380 -
International Journal of Molecular... Nov 2021Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to...
BACKGROUND
Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions.
METHODS
The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice.
RESULTS
The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times.
CONCLUSIONS
Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury.
Topics: Animals; Biglycan; Blood Platelets; Carotid Arteries; Carotid Artery Injuries; Collagen; Cytoskeleton; Extracellular Matrix Proteins; Healthy Volunteers; Hemorrhage; Humans; Integrins; Male; Mice, Inbred C57BL; Platelet Activation; Platelet Adhesiveness; Platelet Membrane Glycoproteins; Thrombosis; Mice
PubMed: 34830059
DOI: 10.3390/ijms222212168 -
Journal of Orthopaedic Research :... Nov 2022Decorin and biglycan are two small leucine-rich proteoglycans (SLRPs) that regulate collagen fibrillogenesis and extracellular matrix assembly in tendon. The objective...
Decorin and biglycan are two small leucine-rich proteoglycans (SLRPs) that regulate collagen fibrillogenesis and extracellular matrix assembly in tendon. The objective of this study was to determine the individual roles of these molecules in maintaining the structural and mechanical properties of tendon during homeostasis in mature mice. We hypothesized that knockdown of decorin in mature tendons would result in detrimental changes to tendon structure and mechanics while knockdown of biglycan would have a minor effect on these parameters. To achieve this objective, we created tamoxifen-inducible mouse knockdown models targeting decorin or biglycan inactivation. This enables the evaluation of the roles of these SLRPs in mature tendon without the abnormal tendon development caused by conventional knockout models. Contrary to our hypothesis, knockdown of decorin resulted in minor alterations to tendon structure and no changes to mechanics while knockdown of biglycan resulted in broad changes to tendon structure and mechanics. Specifically, knockdown of biglycan resulted in reduced insertion modulus, maximum stress, dynamic modulus, stress relaxation, and increased collagen fiber realignment during loading. Knockdown of decorin and biglycan produced similar changes to tendon microstructure by increasing the collagen fibril diameter relative to wild-type controls. Biglycan knockdown also decreased the cell nuclear aspect ratio, indicating a more spindle-like nuclear shape. Overall, the extensive changes to tendon structure and mechanics after knockdown of biglycan, but not decorin, provides evidence that biglycan plays a major role in the maintenance of tendon structure and mechanics in mature mice during homeostasis.
Topics: Animals; Biglycan; Collagen; Disease Models, Animal; Extracellular Matrix; Extracellular Matrix Proteins; Mice; Tamoxifen; Tendons
PubMed: 35171523
DOI: 10.1002/jor.25299