Diverse pathological implications of YKL-40: Answers may lie in ‘outside-in’ signaling

Highlights

• Involvement of YKL-40 as a versatile biomarker in diverse pathologies

• YKL-40-mediated multiple signaling pathways

• Using these pathways to elucidate probable cell surface binding partners of YKL-40

Abstract

The developing paradigms about YKL-40, a member of the “mammalian chitinase-like proteins”, from across the globe, project it as a vital parameter for the detection of disease onset and progression. It is expressed and secreted by cancer cells of different origins along with a variety of non-malignant cells including inflammatory and structural cells. Numerous studies demonstrate that YKL-40 over-expression is associated with increased patient mortality though the cellular receptors responsible for mediating these effects have not yet been identified. The putative YKL-40 ligands are thought to be carbohydrate structures, since it is capable of binding chitin, chito-oligosaccharides and heparin. Binding of collagen to YKL-40, identified it as the only non-carbohydrate extracellular matrix (ECM) ligand for YKL-40. Our broad understanding of YKL-40 as a versatile biomarker and its involvement in activating several signaling pathways make us anticipate that its specific receptors/binding partners may exist on the cell surface also. The cell surface heparan sulfate (HS) moieties seem to be the potential candidates for this role, suggesting that it could interact with HS-proteoglycans. It is recommended to clearly delineate YKL-40-mediated signaling mechanisms before promoting the YKL-40 know-how for translational research, in both diagnostic and therapeutic applications. The present review provides an overview of YKL-40 as a versatile biomarker, discussing the related pathological mechanisms and aims to reassess and unify the already proposed diverse hypotheses in YKL-40-regulated signaling mechanisms.

Introduction

YKL-40, an extensively discussed biomarker, playing an important pathological role in a myriad of diseases belongs to the glycosyl hydrolases family 18, which includes the chitinases [1]. Chitin, a polymer of N-acetyl glucosamine, is the second most abundant polysaccharide in nature, following cellulose. It is found in the walls of fungi; the exoskeleton of crabs, shrimp and insects; the micro filarial sheath of parasitic nematodes; and the lining of the digestive tracts of many insects [2], [3]. Chitin accumulation is regulated by the balance of chitin synthase-mediated biosynthesis and degradation by chitinases. Although humans do not have chitin and chitin synthase, studies have shown that they do express true chitinases, including acidic mammalian chitinase (AMCase) and chitotriosidase [3], [4]. YKL-40 was first discovered as a 40 kDa protein secreted by the MG63 human osteosarcoma cell line [5]. The CHI3L1 gene for human YKL-40 is localized in a highly conserved area on chromosome 1q31-q32 [6] and its crystal structure has already been described [7]. Though YKL-40 contains highly conserved chitin-binding domains; it functionally lacks chitinase activity [8]. YKL-40 is also named as human cartilage glycoprotein-39 (HC-gp39) [9], 38-kDa heparin-binding glycoprotein (gp38k) [10], chitinase-3-like-1 (CHI3L1) [11], and chondrex [12]. Although the biological characteristics of YKL-40 and other chitinase-like proteins (CLPs) remain partly understood, its diverse roles in cell proliferation, differentiation, survival, inflammation and tissue remodeling have been suggested [13]. Aberrant expression of YKL-40 is associated with the pathogenesis of an array of human diseases (Fig. 1) [14], [15], [16], [17], [18] and its use as a biomarker is largely agreed upon [19]. Some of the primary immune cells like macrophages and neutrophils have been shown to secrete YKL-40, along with some cancer cells [11], [20], [21]. Biologically, YKL-40 has been shown to activate cancer signaling pathways and promote tumor angiogenesis [22], [23] and also a wide range of inflammatory responses (Fig. 2). Elevated serum YKL-40 levels are also associated with a wide range of inflammatory diseases. YKL-40 can act as a fibroblast mitogen, activating several signaling pathways; however, no cell surface receptor for YKL-40 has been identified so far. Type I collagen is its only known ECM protein-binding partner till date [24]. Though the exact functions of YKL-40 remain enigmatic, its ability to bind both proteins and carbohydrates allows us to view it as a linking factor between proteomics and glycomics. It remains to be determined whether routine measurement of YKL-40 can provide useful clinical information for risk assessment in patients, or for monitoring patients after intervention with different therapies. The present article provides an overview of YKL-40, as a versatile biomarker, discussing the related pathological mechanisms.