Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology

Schaefer, Liliana; Tredup, Claudia; Gubbiotti, Maria A.; Iozzo, Renato V.

doi:10.1111/febs.13963

Cited by 131 publications

(141 citation statements)

References 150 publications

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“…The use of a ubiquitous Cre also excludes translation and secretion at other sites. There is evidence that SLRPs from other sites can be deposited into remote tissues, particularly during inflammatory responses [28, 29]. Also, systemically administered SLRPs can be integrated into tissues [30].…”

Section: Discussionmentioning

confidence: 99%

Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons

et al. 2017

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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 toward 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.

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Section: Discussionmentioning

confidence: 99%

Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons

et al. 2017

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“…In more recent times a major breakthrough came from the appreciation that PGs/GAGs were not merely supportive scaffolding components of the ECM. [15,17,[19][20][21][22] Articular cartilage has an inherently low capacity for self-repair and degeneration of cartilage in diseases such as osteoarthritis (OA) are painful debilitating conditions leading to considerable interest in repair biology for the development of therapies to prevent disease progression to end stage OA. This has led to the realization that PGs/GAGs could potentially be used in a therapeutic mode to promote repair of tissue defects [12][13][14][15][16][17][18] and the reattainment of functional properties in tissues that had undergone degradative changes due to disease.…”

Section: Introductionmentioning

confidence: 99%

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

Hayes

Melrose

2019

Advanced Therapeutics

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The aim of this study is to review developments in glycosaminoglycan and proteoglycan research relevant to cartilage repair biology and in particular the treatment of osteoarthritis (OA). Glycosaminoglycans decorate a diverse range of extracellular matrix and cell associated proteoglycans conveying structural organization and physico-chemical properties to tissues. They play key roles mediating cellular interactions with bioactive growth factors, cytokines, and morphogenetic proteins, and structural fibrillar collagens, cell interactive and extracellular matrix proteoglycans, and glycoproteins which define tissue function. Proteoglycan degradation detrimentally affects tissue functional properties. Therapeutic strategies have been developed to counter these degenerative changes. Neo-proteoglycans prepared from chondroitin sulfate or hyaluronan and hyaluronan or collagen-binding peptides emulate the interactive, water imbibing, weight bearing, and surface lubricative properties of native proteoglycans. Many neo-proteoglycans outperform native proteoglycans in terms of water imbibition, matrix stabilization, and resistance to proteolytic degradation. The biospecificity of recombinant proteoglycans however, provides precise attachment to native target molecules. Visco-supplements augmented with growth factors/therapeutic cells, hyaluronan, and lubricin (orthobiologicals) have the capacity to lubricate and protect cartilage, control inflammation, and promote cartilage repair and regeneration of early cartilage lesions and may represent a more effective therapeutic approach to the treatment of mild to moderate OA and deserve further study.Similar protective perineural net structures assembled from the lectican proteoglycan family and HA also occur in the CNS/PNS. These so called perineuronal nets are visualized by immunolocalization of MAb 1B5 (+) epitope in rat brain (e) and pericellular 1B5(+) epitope expression by isolated neurons (f). Scale bars 100 µm.

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“…The structural motifs of biglycan protein and the adapter molecules involved in these interactions need further investigations. By selective engagement of TLRs and their adaptor molecules biglycan tightly regulates inflammatory outcome [6,7,11,12]. Accordingly, biglycan-induced recruitment of macrophages to the kidney depends on biglycan-triggered transcription and secretion of macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 [4,5,6,9,13,14].…”

Section: Introductionmentioning

confidence: 99%

Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants

Hsieh

Nastase

Roedig

et al. 2017

IJMS

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Abstract: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 biglycanand SphK1-driven extracellular matrix-and lipid-signaling. Thus, SphK1 may represent a new target for therapeutic intervention in biglycan-evoked inflammatory conditions.

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Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology

Cited by 131 publications

References 150 publications

Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons

Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants

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