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1.  Biglycan 
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.
doi:10.1369/0022155412456380
PMCID: PMC3527886  PMID: 22821552
extracellular matrix; proteoglycan; Toll-like receptor; inflammasome; TGFβ; inflammation; bone; skeletal muscle; Duchenne’s muscular dystrophy; sepsis; Wnt
2.  Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation 
Cell Cycle  2012;11(11):2084-2091.
Inflammation is not only a defensive mechanism against microbial invasion, but also frequently represents a critical response to tissue injury under sterile conditions. It is now well established that tissue injury leads to the release of endogenous molecules of intra- and extracellular origin acting as damage-associated molecular patterns (DAMPs). The small leucine-rich proteoglycans (SLRPs) can act as powerful DAMPs following their proteolytical release from the extracellular matrix. Recent investigations of SLRP signaling networks revealed new levels of complexity, showing that SLRPs can cluster different types of receptors and orchestrate a host of downstream signaling events. This review will summarize the evidence for the multifunctional proinflammatory signaling properties of the two archetypal SLRPs, biglycan and decorin. These secreted proteoglycans link the innate to the adaptive immune response and operate in a broad biological context, encompassing microbial defense, tumor growth and autoimmunity.
doi:10.4161/cc.20316
PMCID: PMC3368860  PMID: 22580469
biglycan; decorin; Inflammasome; macrophage; micro-RNA-21; PDCD4; sepsis; TGFβ; toll-like receptor; tumor
3.  Decorin Protein Core Affects the Global Gene Expression Profile of the Tumor Microenvironment in a Triple-Negative Orthotopic Breast Carcinoma Xenograft Model 
PLoS ONE  2012;7(9):e45559.
Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties.
doi:10.1371/journal.pone.0045559
PMCID: PMC3446891  PMID: 23029096
4.  The proteoglycan biglycan enhances antigen-specific T cell activation via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis 
Biglycan is a proteoglycan ubiquitously present in extracellular matrix of a variety of organs including heart and has been reported to be overexpressed in myocardial infarction. Myocardial infarction may be complicated by perimyocarditis through to date unclear mechanisms. Our aim was to investigate the capacity of TLR2/TLR4 ligand biglycan to enhance the presentation of specific Ags released upon cardiomyocyte necrosis. In vitro, Ova-pulsed bone-marrow derived dendritic cells from WT (C57BL/6), TLR2-, TLR4-, MyD88- or TRIF- deficient mice were co-treated with LPS, biglycan or vehicle and incubated with Ova-recognizing MHCI- or MHCII-restricted T cells. Biglycan enhanced Ova-specific cross-priming by more than 80% to MHCI-restricted T cells in both TLR2 - and TLR4 – pathway dependent manner. Accordingly, biglycan-induced cross-priming by both MyD88- and TRIF-deficient DCs was strongly diminished. Ova-specific activation of MHCII-restricted T cells was predominantly TLR4-dependent. Our first in vivo correlate was a model of experimental autoimmune perimyocarditis triggered by injection of cardiac-Ag pulsed DCs (BALB/c). Biglycan-treated DCs triggered perimyocarditis in extent and intensity comparable to LPS-treated DCs (average scores 1.3±0.3 and 1.5±0.4, respectively). Substitution with TLR4-deficient DCs abolished this effect. In a second in vivo approach, WT and biglycan-deficient mice were followed two weeks after induction of myocardial infarction. WT mice demonstrated significantly higher myocardial T-lymphocyte infiltration in comparison to biglycan-deficient animals. We conclude that TLR2/4 ligand biglycan, a component of the myocardial matrix, may enhance Ag-specific T cell priming via MyD88 and TRIF and stimulate autoimmune perimyocarditis.
doi:10.4049/jimmunol.1003478
PMCID: PMC3428142  PMID: 22095710
5.  SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis 
Nature  2011;471(7340):637-641.
SHARPIN is a ubiquitin-binding and ubiquitin-like domain-containing protein which, when mutated in mice, results in immune system disorders and multiorgan inflammation1,2. Here we report that SHARPIN functions as a novel component of the Linear Ubiquitin Chain Assembly Complex (LUBAC) and that the absence of SHARPIN causes disregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis in SHARPIN deficient mice. Upon binding to the LUBAC subunit HOIP, SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Co-expression of SHARPIN and HOIP promotes linear ubiquitylation of NEMO, an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, while SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages, and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L, another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon TNFα stimulation via FADD- and Caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.
doi:10.1038/nature09814
PMCID: PMC3085511  PMID: 21455181
6.  Proteoglycans in health and disease: Novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans 
The Febs Journal  2010;277(19):3864-3875.
The small leucine-rich proteoglycans (SLRPs) are involved in many aspects of mammalian biology, both in health and disease. They are now being recognized as key signaling molecules with an expanding repertoire of molecular interactions affecting not only growth factors, but also various receptors involved in controlling cell growth, morphogenesis and immunity. The complexity of SLRP signaling and the multitude of affected signaling pathways can be reconciled with a hierarchical affinity-based interaction of various SLRPs in a cell- and tissue-specific context. Below, we review this interacting network, describe new relationships of the SLRPs with tyrosine kinase and Toll-like receptors and critically assess their roles in cancer and innate immunity.
doi:10.1111/j.1742-4658.2010.07797.x
PMCID: PMC3000440  PMID: 20840584
Decorin; biglycan; lumican; signal transduction; EGFR; Met; IGF-IR; Toll-like receptor; cancer; inflammation
7.  Nephronectin regulates atrioventricular canal differentiation via Bmp4-Has2 signaling in zebrafish 
Development (Cambridge, England)  2011;138(20):4499-4509.
The extracellular matrix is crucial for organogenesis. It is a complex and dynamic component that regulates cell behavior by modulating the activity, bioavailability and presentation of growth factors to cell surface receptors. Here, we determined the role of the extracellular matrix protein Nephronectin (Npnt) in heart development using the zebrafish model system. The vertebrate heart is formed as a linear tube in which myocardium and endocardium are separated by a layer of extracellular matrix termed the cardiac jelly. During heart development, the cardiac jelly swells at the atrioventricular (AV) canal, which precedes valve formation. Here, we show that Npnt expression correlates with this process. Morpholino-mediated knockdown of Npnt prevents proper valve leaflet formation and trabeculation and results in greater than 85% lethality at 7 days post-fertilization. The earliest observed phenotype is an extended tube-like structure at the AV boundary. In addition, the expression of myocardial genes involved in cardiac valve formation (cspg2, fibulin 1, tbx2b, bmp4) is expanded and endocardial cells along the extended tube-like structure exhibit characteristics of AV cells (has2, notch1b and Alcam expression, cuboidal cell shape). Inhibition of has2 in npnt morphants rescues the endocardial, but not the myocardial, expansion. By contrast, reduction of BMP signaling in npnt morphants reduces the ectopic expression of myocardial and endocardial AV markers. Taken together, our results identify Npnt as a novel upstream regulator of Bmp4-Has2 signaling that plays a crucial role in AV canal differentiation.
doi:10.1242/dev.067454
PMCID: PMC3253110  PMID: 21937601
Nephronectin; Atrioventricular canal; Bmp4; Zebrafish
8.  The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis 
The Journal of Clinical Investigation  2010;120(12):4251-4272.
CXCL13 is a key B cell chemoattractant and marker of disease activity in patients with SLE; however, the mechanism of its induction has not been identified yet. Here, we have shown that the proteoglycan biglycan triggers CXCL13 expression via TLR2/4 in macrophages and dendritic cells. In vivo, levels of biglycan were markedly elevated in the plasma and kidneys of human SLE patients and lupus-prone (MRL/lpr) mice. Overexpression of soluble biglycan in MRL/lpr mice raised plasma and renal levels of CXCL13 and caused accumulation of B cells with an enhanced B1/B cell ratio in the kidney, worsening of organ damage, and albuminuria. Importantly, biglycan also triggered CXCL13 expression and B cell infiltration in the healthy kidney. Conversely, biglycan deficiency improved systemic and renal outcome in lupus-prone mice, with lower levels of autoantibodies, less enlargement of the spleen and lymph nodes, and reduction in renal damage and albuminuria. This correlated with a marked decline in circulating and renal CXCL13 and a reduction in the number of B cells in the kidney. Collectively, our results describe what we believe to be a novel mechanism for the regulation of CXCL13 by biglycan, a host-derived ligand for TLR2/4. Blocking biglycan-TLR2/4 interactions might be a promising strategy for the management of SLE and other B cell–mediated inflammatory disease entities.
doi:10.1172/JCI42213
PMCID: PMC2993585  PMID: 21084753
9.  Inhibition of the Soluble Epoxide Hydrolase Promotes Albuminuria in Mice with Progressive Renal Disease 
PLoS ONE  2010;5(8):e11979.
Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered reno-protective. EETs are degraded by the enzyme soluble epoxide hydrolase (sEH) and sEH inhibitors are considered treatment for chronic renal failure (CRF). We determined whether sEH inhibition attenuates the progression of CRF in the 5/6-nephrectomy model (5/6-Nx) in mice. 5/6-Nx mice were treated with a placebo, an ACE-inhibitor (Ramipril, 40 mg/kg), the sEH-inhibitor cAUCB or the CYP-inhibitor fenbendazole for 8 weeks. 5/6-Nx induced hypertension, albuminuria, glomerulosclerosis and tubulo-interstitial damage and these effects were attenuated by Ramipril. In contrast, cAUCB failed to lower the blood pressure and albuminuria was more severe as compared to placebo. Plasma EET-levels were doubled in 5/6 Nx-mice as compared to sham mice receiving placebo. Renal sEH expression was attenuated in 5/6-Nx mice but cAUCB in these animals still further increased the EET-level. cAUCB also increased 5-HETE and 15-HETE, which derive from peroxidation or lipoxygenases. Similar to cAUCB, CYP450 inhibition increased HETEs and promoted albuminuria. Thus, sEH-inhibition failed to elicit protective effects in the 5/6-Nx model and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway.
doi:10.1371/journal.pone.0011979
PMCID: PMC2915917  PMID: 20694143
10.  The matricellular functions of small leucine-rich proteoglycans (SLRPs) 
The small leucine-rich proteoglycans (SLRPs) are biologically active components of the extracellular matrix (ECM), consisting of a protein core with leucine rich-repeat (LRR) motifs covalently linked to glycosaminoglycan (GAG) side chains. The diversity in composition resulting from the various combinations of protein cores substituted with one or more GAG chains along with their pericellular localization enables SLRPs to interact with a host of different cell surface receptors, cytokines, growth factors, and other ECM components, leading to modulation of cellular functions. SLRPs are capable of binding to: (i) different types of collagens, thereby regulating fibril assembly, organization, and degradation; (ii) Toll-like receptors (TLRs), complement C1q, and tumor necrosis factor-alpha (TNFα), regulating innate immunity and inflammation; (iii) epidermal growth factor receptor (EGF-R), insulin-like growth factor receptor (IGF-IR), and c-Met, influencing cellular proliferation, survival, adhesion, migration, tumor growth and metastasis as well as synthesis of other ECM components; (iv) low-density lipoprotein receptor-related protein (LRP-1) and TGF-β, modulating cytokine activity and fibrogenesis; and (v) growth factors such as bone morphogenic protein (BMP-4) and Wnt-I-induced secreted protein-1 (WISP-1), controlling cell proliferation and differentiation. Thus, the ability of SLRPs, as ECM components, to directly or indirectly regulate cell-matrix crosstalk, resulting in the modulation of various biological processes, aptly qualifies these compounds as matricellular proteins.
doi:10.1007/s12079-009-0066-2
PMCID: PMC2778586  PMID: 19809894
Biglycan; Decorin; Lumican; Inflammation; Fibrosis; Innate immunity
11.  The matricellular functions of small leucine-rich proteoglycans (SLRPs) 
The small leucine-rich proteoglycans (SLRPs) are biologically active components of the extracellular matrix (ECM), consisting of a protein core with leucine rich-repeat (LRR) motifs covalently linked to glycosaminoglycan (GAG) side chains. The diversity in composition resulting from the various combinations of protein cores substituted with one or more GAG chains along with their pericellular localization enables SLRPs to interact with a host of different cell surface receptors, cytokines, growth factors, and other ECM components, leading to modulation of cellular functions. SLRPs are capable of binding to: (i) different types of collagens, thereby regulating fibril assembly, organization, and degradation; (ii) Toll-like receptors (TLRs), complement C1q, and tumor necrosis factor-alpha (TNFα), regulating innate immunity and inflammation; (iii) epidermal growth factor receptor (EGF-R), insulin-like growth factor receptor (IGF-IR), and c-Met, influencing cellular proliferation, survival, adhesion, migration, tumor growth and metastasis as well as synthesis of other ECM components; (iv) low-density lipoprotein receptor-related protein (LRP-1) and TGF-β, modulating cytokine activity and fibrogenesis; and (v) growth factors such as bone morphogenic protein (BMP-4) and Wnt-I-induced secreted protein-1 (WISP-1), controlling cell proliferation and differentiation. Thus, the ability of SLRPs, as ECM components, to directly or indirectly regulate cell-matrix crosstalk, resulting in the modulation of various biological processes, aptly qualifies these compounds as matricellular proteins.
doi:10.1007/s12079-009-0066-2
PMCID: PMC2778586  PMID: 19809894
Biglycan; Decorin; Lumican; Inflammation; Fibrosis; Innate immunity
12.  WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis 
Idiopathic pulmonary fibrosis (IPF) is characterized by distorted lung architecture and loss of respiratory function. Enhanced (myo)fibroblast activation, ECM deposition, and alveolar epithelial type II (ATII) cell dysfunction contribute to IPF pathogenesis. However, the molecular pathways linking ATII cell dysfunction with the development of fibrosis are poorly understood. Here, we demonstrate, in a mouse model of pulmonary fibrosis, increased proliferation and altered expression of components of the WNT/β-catenin signaling pathway in ATII cells. Further analysis revealed that expression of WNT1-inducible signaling protein–1 (WISP1), which is encoded by a WNT target gene, was increased in ATII cells in both a mouse model of pulmonary fibrosis and patients with IPF. Treatment of mouse primary ATII cells with recombinant WISP1 led to increased proliferation and epithelial-mesenchymal transition (EMT), while treatment of mouse and human lung fibroblasts with recombinant WISP1 enhanced deposition of ECM components. In the mouse model of pulmonary fibrosis, neutralizing mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT. More importantly, these changes in gene expression were associated with marked attenuation of lung fibrosis, including decreased collagen deposition and improved lung function and survival. Our study thus identifies WISP1 as a key regulator of ATII cell hyperplasia and plasticity as well as a potential therapeutic target for attenuation of pulmonary fibrosis.
doi:10.1172/JCI33950
PMCID: PMC2662540  PMID: 19287097
13.  Reply 
doi:10.1093/ndt/gfn263
PMCID: PMC2542411
14.  The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages 
Journal of Clinical Investigation  2005;115(8):2223-2233.
Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-κB and thereby stimulating the expression of TNF-α and macrophage inflammatory protein–2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2–/–, and myeloid differentiation factor 88–/– (MyD88–/–) macrophages and completely abolished in TLR2–/–/TLR4-M macrophages. Biglycan-null mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-α and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-α and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.
doi:10.1172/JCI23755
PMCID: PMC1174916  PMID: 16025156

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