Key roles for the small leucine-rich proteoglycans in renal and pulmonary pathophysiology

Abstract

Background: Small leucine-rich proteoglycans (SLRPs) are molecules that have signaling roles in a multitude of biological processes. In this respect, SLRPs play key roles in the evolution of a variety of diseases throughout the human body.

Scope of review: We will critically review current developments in the roles of SLRPs in several types of disease of the kidney and lungs. Particular emphasis will be given to the roles of decorin and biglycan, the best characterized members of the SLRP gene family.

Major conclusions: In both renal and pulmonary disorders, SLRPs are essential elements that regulate several pathophysiological processes including fibrosis, inflammation and tumor progression. Decorin has remarkable antifibrotic and antitumorigenic properties and is considered a valuable potential treatment of these diseases. Biglycan can modulate inflammatory processes in lung and renal inflammation and is a potential target in the treatment of inflammatory conditions.

General significance: SLRPs can serve as either treatment targets or as potential treatment in renal or lung disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Keywords: Biglycan; Cancer; Decorin; Extracellular matrix; TGF-β; Toll-like receptor.

Figure 1. Decorin and biglycan signaling in fibrosis and inflammation

In renal fibroblasts, through binding to IGF-IR and via the activation of the PI3K and Akt/PKB pathways and mTOR, decorin induces the translation of fibrillin-1, a regulator of TGF-β availability. In tubular epithelial cells decorin reduces apoptosis through interaction with IGF-IR and activation of downstream PI3K/Akt/PKB pathway. Additionally, decorin can bind CTGF (CCN2) and reduce the CTGF-induced levels of collagen III and fibronectin. Soluble biglycan binds to both TLR2 and 4 and via MyD88 activates the Erk, p38 and NF-κB pathways. This leads to the synthesis of pro-IL-1β, TNF-α, and the chemoattractants CXCL1, CXCL2, CCL3 and CCL5. The inflammasome complex NLRP3, ASC and caspase-1 can also be induced by soluble biglycan, leading to activation of caspase-1 which cleaves pro-IL-1β to mature IL-1β. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; CCL, Chemokine (C-C motif) ligand; CTGF/CCN2, connective tissue growth factor; CXCL, Chemokine (C-X-C motif) ligand; Erk, extracellular-signal-regulated kinase; IGF-IR, insulin-like growth factor type I receptor; IL-1β, interleukin 1β; mTOR, mammalian target of rapamycin; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; NLRP3, NLR family, pyrin domain–containing 3; PI3K, phosphatidylinositide 3-kinase; TGF-β, transforming growth factor-β; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α.

Figure 2. Decorin’s interference with signaling in cancer

In cancer cells, decorin binds to IGF-IR and to its ligand IGF-I at different binding sites and decreases both IGF-I-induced MAPK and Akt pathways activation leading to less level of p90RSK and p70S6K, respectively. Through binding to EGFR, decorin leads to receptor internalization and its lysosomal degradation. Following binding, EGFR gets phosphorylated and Erk1/2 are activated, leading to the transcription of the CDKN1A gene corresponding to cyclin-dependent kinase inhibitor 1, p21^WAF1. When the HGF receptor Met is activated following Serine62 phosphorylation, Myc is translocated to the nucleus where induces the synthesis of AP4, a repressor for the CDKN1A gene. At the same time β-catenin is also translocated to the nucleus where it is recruited to and activates TCF/LEF-related gene transcription and induces the synthesis of tumor-associated genes such as c-MYC and MYCN. When decorin binds to Met following the phosphorylation of Myc (at Threonine58) and β-catenin, both are triggered to proteasomal degradation. Through Met, decorin inhibits proangiogenic factors such as HIF-1α. Alternatively, decorin interacts with VEGFR2 thereby leading to rapid phosphorylation of AMPK and increased levels of Peg3 as well as Peg3-dependent expression of autophagy-related genes BECN1 and MAP1LC3a. This mechanism is upstream of autophagy induction under decorin stimulation. Decorin binds TLR2 and TLR4, activates MAPKs and NF-κB and induces the transcription of the TNF, IL12B, IL10 and PDCD4 genes. Decorin-induced PDCD4 leads to translational repression of IL-10. By inhibiting TGF-β signaling, decorin decreases the abundance of oncogenic microRNA-21 (miR-21) and prevents the miR-21-dependent translational repression of PDCD4 and thus reduces the levels of IL-10 protein. Abbreviations: AMPK, 5′ adenosine monophosphate-activated protein kinase; AP4, activating enhancer-binding protein; BECN1, Beclin1; CDKN1A, cyclin-dependent kinase inhibitor 1; EGFR, epidermal growth factor receptor; Erk, extracellular-signal-regulated kinase; HGF, hepatocyte growth factor; HIF-1α, hypoxia inducible factor-1α; IGF-I, insulin growth factor type I; IGF-IR, insulin-like growth factor type I receptor; IL, interleukin; MAP1LC3a, microtubule-associated protein 1 light chain 3 alpha; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PDCD4, programmed cell death 4; Peg3, Paternally-expressed gene 3; TCF/LEF, lymphoid enhancer-binding factor/T-cell-specific factor; TNF-α, tumor necrosis factor; TGF-β, transforming growth factor-β; VEGFR2, vascular endothelial growth factor receptor.