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The Journal of Histochemistry and... Nov 2020Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of... (Review)
Review
Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of Biglycan and other related SLRPs in mineralizing tissues of the skeleton. The review is divided into sections that include Biglycan's role in structural biology, signaling, craniofacial and long bone homeostasis, remodeled skeletal tissues, and in human genetics. While many cell types in the skeleton are now known to be affected by Biglycan, there are still unanswered questions about its mechanism of action(s).
Topics: Animals; Biglycan; Humans; Muscle, Skeletal
PubMed: 32623936
DOI: 10.1369/0022155420937371 -
Matrix Biology : Journal of the... Jun 2021Soluble biglycan, a small leucine-rich proteoglycan, plays a significant role in several pathologies as it has emerged as an extracellular matrix-derived... (Review)
Review
Soluble biglycan, a small leucine-rich proteoglycan, plays a significant role in several pathologies as it has emerged as an extracellular matrix-derived danger-associated molecular pattern. Biglycan is released from the extracellular matrix in response to tissue injury and, as a canonical danger signal, interacts with innate immune receptors, Toll-like receptors 2 and 4, thereby triggering a sustained inflammatory response. Recent evidence indicates that biglycan acts as a molecular switch between inflammation and autophagy by a specific interaction with the Toll-like co-receptor CD14 and CD44, respectively. Biglycan-evoked autophagy further contributes to the anti-inflammatory M2 macrophage polarization, inflammation resolution and tissue repair. These multivalent roles of soluble biglycan have been well characterized in inflammatory kidney diseases. In chronic liver diseases, increased levels of soluble biglycan have been described for years, leading to utilization of biglycan serum levels as a non-invasive biomarker for fibrosis. Hepatorenal dysfunction represents a classic example of inter-organ crosstalk, in which functional and molecular alterations of the cirrhotic liver can promote the development of renal failure. In patients with liver cirrhosis, development of hepatorenal syndrome is associated with high mortality. In this review, we will discuss the crucial role of soluble biglycan in inflammation and autophagy and its possible implications for hepatorenal dysfunction. We propose a novel concept of hepatorenal crosstalk, that is, biglycan produced by the cirrhotic liver could constitute a circulating "messenger" for the kidneys triggering inflammation and/or autophagy ultimately affecting disease outcome.
Topics: Autophagy; Biglycan; Humans; Inflammation; Liver; Toll-Like Receptors
PubMed: 34118408
DOI: 10.1016/j.matbio.2021.06.001 -
Molecular and Cellular Biochemistry Nov 2021Extracellular matrix (ECM) plays an important role in the structural organization of tissue and delivery of external cues to the cell. Biglycan, a class I small... (Review)
Review
Extracellular matrix (ECM) plays an important role in the structural organization of tissue and delivery of external cues to the cell. Biglycan, a class I small leucine-rich proteoglycans (SLRP), is a key component of the ECM that participates in scaffolding the collagen fibrils and mediates cell signaling. Dysregulation of biglycan expression can result in wide range of clinical conditions such as metabolic disorder, inflammatory disorder, musculoskeletal defects and malignancies. In this review, we aim to update our current understanding regarding the link between altered expression of biglycan and different clinicopathological states. Biglycan interacts with toll like receptors (TLR)-2 and TLR-4 on the immune cells which initiates inflammation and aggravates inflammatory disorders. ECM unbound soluble biglycan acts as a DAMP (danger associated molecular pattern) resulting in sterile inflammation. Dysregulation of biglycan expression is also observed in inflammatory metabolic conditions such as atherosclerosis and obesity. In cancer, high-biglycan expression facilitates tumor growth, invasion and metastasis which is associated with poor clinical outcome. As a pivotal structural component of the ECM, biglycan strengthens the musculoskeletal system and its absence is associated with musculoskeletal defects. Thus, SLRP biglycan is a potential marker which is significantly altered in different clinicopathological states.
Topics: Animals; Biglycan; Biomarkers; Extracellular Matrix Proteins; Humans; Inflammation; Metabolic Diseases; Neoplasms; Small Leucine-Rich Proteoglycans; Toll-Like Receptor 2; Toll-Like Receptor 4
PubMed: 34181183
DOI: 10.1007/s11010-021-04216-z -
American Journal of Physiology. Cell... Jun 2022The class I small leucine-rich proteoglycan biglycan is a crucial structural extracellular matrix component that interacts with a wide range of extracellular matrix... (Review)
Review
The class I small leucine-rich proteoglycan biglycan is a crucial structural extracellular matrix component that interacts with a wide range of extracellular matrix molecules. In addition, biglycan is involved in sequestering growth factors such as transforming growth factor-β and bone morphogenetic proteins and thereby regulating pathway activity. Biglycan consists of a 42-kDa core protein linked to two glycosaminoglycan side chains and both are involved in protein interactions. Biglycan is encoded by the gene located on the X-chromosome and is expressed in various tissues, including vascular tissue, skin, brain, kidney, lung, the immune system, and the musculoskeletal system. Although an increasing amount of data on the biological function of biglycan in the vasculature has been produced, its role in thoracic aortic aneurysms is still not fully elucidated. This review focuses on the role of biglycan in the healthy thoracic aorta and the development of thoracic aortic aneurysm and dissections in both mice and humans.
Topics: Animals; Aorta, Thoracic; Biglycan; Bone Morphogenetic Proteins; Extracellular Matrix Proteins; Mice; Signal Transduction; Transforming Growth Factor beta
PubMed: 35476501
DOI: 10.1152/ajpcell.00036.2022 -
Connective Tissue Research Jan 2020: Biglycan is a proteoglycan of the small leucine-rich repeat family. It is present in all connective tissues and plays key structural and signaling roles. This review... (Review)
Review
: Biglycan is a proteoglycan of the small leucine-rich repeat family. It is present in all connective tissues and plays key structural and signaling roles. This review aimed to compile available evidence in the characteristics and distribution of biglycan and its glycosylated and non-glycosylated forms in connective tissues with a specific focus on the contribution to homeostasis of bone and changes of biglycan structure with aging.: The Pubmed database was searched and included the terms "biglycan", "proteoglycans", "glycosaminoglycans", "bone", "osteoblast", "osteocyte", "osteoclast", "aging", "inflammation", "cartilage". Abstracts were appraised and a series of original articles and reviews studied to generate this narrative review.: Based on the search, biglycan significantly affects bone development and homeostasis and can be significantly changed by the aging process in several connective tissues, which in turn affects the behavior of tissue and cell responses in aged networks. Further, as the understanding of the various forms of biglycan is expanded and the function of its components is dissected, this proteoglycan can potentially serve as a therapeutic or biomarker molecule to detect tissue destruction.: Biglycan is a key player in skeletal bone homeostasis, and overall, there is more evidence on the role of biglycan in development and less in the adult physiological or diseased young and aged systems. Further understanding of its conformation, degradation peptides and post-translational modifications will be required to understand the role of biglycan in bone maintenance and to support the development of treatments for age-related bone dysfunctions.
Topics: Aging; Animals; Biglycan; Bone and Bones; Extracellular Matrix Proteins; Homeostasis; Humans
PubMed: 31597498
DOI: 10.1080/03008207.2019.1669577 -
Oncoimmunology 2022Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and...
Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.
Topics: Biglycan; Cancer-Associated Fibroblasts; Fibroblasts; Humans; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 35003899
DOI: 10.1080/2162402X.2021.2020984 -
Biochimica Et Biophysica Acta.... Feb 2020Atherosclerosis (ATH) is a chronic, dynamic, evolutive process involving morphological and structural subversion of artery walls, leading to the formation of... (Review)
Review
Atherosclerosis (ATH) is a chronic, dynamic, evolutive process involving morphological and structural subversion of artery walls, leading to the formation of atherosclerotic plaques. ATH generally initiates during the childhood, occurring as a result of a number of changes in the intima tunica and in the media of arteries. A key event occurring during the pathobiology of ATH is the accumulation of lipoproteins in the sub-intimal spaces mediated by extracellular matrix (ECM) molecules, especially by the chondroitin sulfate/dermatan sulfate (CS/DS) -containing proteoglycans (CS/DSPGs). Among them, the proteoglycan biglycan (BGN) is critically involved in the onset and progression of ATH and evidences show that BGN represents the missing link between the pro-atherogenic status induced by both traditional and non-traditional cardiovascular risk factors and the development and progression of vascular damage. In the light of these findings, the role of BGN in dyslipidemia, hypertension, cigarette smoking, diabetes, chronic kidney disease and inflammatory status is briefly analyzed and discussed in order to shed new light on the underlying mechanisms governing the association between BGN and ATH.
Topics: Animals; Atherosclerosis; Biglycan; Cigarette Smoking; Diabetes Mellitus; Disease Models, Animal; Disease Progression; Dyslipidemias; Humans; Hypertension; Inflammation; Lipoproteins; Prevalence; Renal Insufficiency, Chronic; Risk Factors
PubMed: 31672572
DOI: 10.1016/j.bbalip.2019.158545 -
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 -
Clinica Chimica Acta; International... Apr 2019The extracellular matrix (ECM) prevents invasion of tumour cells and possesses an intrinsic mechanism to down-regulate signalling processes that promote cancer... (Review)
Review
The extracellular matrix (ECM) prevents invasion of tumour cells and possesses an intrinsic mechanism to down-regulate signalling processes that promote cancer proliferation. Small Leucine Rich Proteoglycans (SLRPs) are ubiquitous ECM components involved in matrix structural organization and as such can potentially regulate cancer cell multiplication, angiogenesis and migration. Decorin, a class I SLRP that modulates collagen fibrillogenesis, also functions as a natural pan-tyrosine kinase inhibitor to reduce tumour growth. In fact, decreased decorin expression has been associated with tumour aggressiveness and lower survival. In contrast, biglycan, another class I SLRP, was highly expressed in cancer and was associated with metastatic activity and lower survival. Tissue expression of lumican, a class II SLRP, was associated with clinical outcome and appears tumour specific. Recently, decorin, biglycan and lumican were found to be potential biomarkers in bladder cancer. This review updates our current understanding on the molecular interplay and significance of decorin, biglycan and lumican expression in cancer.
Topics: Animals; Biglycan; Decorin; Gene Expression Regulation, Neoplastic; Humans; Leucine; Lumican; Neoplasms
PubMed: 30629950
DOI: 10.1016/j.cca.2019.01.003 -
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