Perlecan, the “jack of all trades” proteoglycan of cartilaginous weight‐bearing connective tissues

Abstract

Perlecan is a ubiquitous proteoglycan of basement membrane and vascularized tissues but is also present in articular cartilage, meniscus and intervertebral disc, which are devoid of basement membrane and predominantly avascular. It is a prominent pericellular proteoglycan in the transitory matrix of the cartilaginous rudiments that develop into components of diarthrodial joints and the axial skeleton, and it forms intricate perichondrial vessel networks that define the presumptive articulating surfaces of developing joints and line the cartilage canals in cartilaginous rudiments. Such vessels have roles in the nutrition of the expanding cell numbers in the developing joint. Perlecan sequesters a number of growth factors pericellularly (FGFs, PDGF, VEGF and CTGF) and through these promotes cell signalling, cell proliferation and differentiation. Perlecan also interacts with a diverse range of extracellular matrix proteins, stabilising and organising the ECM, and promoting collagen fibrillogenesis. Perlecan is a prominent pericellular component of mesenchymal cells from their earliest developmental stages through to maturation, forming cell-cell and cell-ECM interconnections that are suggestive of a role in mechanosensory processes important to tissue homeostasis.

Recent advances in annular pathobiology provide insights into rim-lesion mediated intervertebral disc degeneration and potential new approaches to annular repair strategies

“…Our laboratory has embarked on a series of studies in the last few years to better understand the role of a multifunctional HS-proteoglycan, perlecan in FGF growth factor signalling in cartilaginous tissues and to assess how this regulates chondrogenic events relevant in annular development and remodelling [78]. Perlecan is a, large, modular, multifunctional proteoglycan with a 467-kDa protein core containing five distinct domains with homology to the laminin A chain, low density lipoprotein receptor, neural cell adhesion molecule and epidermal growth factor [62,94,102].…”

“…The low density lipoprotein (LDL) repeats in perlecan domain II bind connective tissue growth factor (CTGF) [2,101], CTGF modulates bone morphogenetic protein (BMP) and transforming growth factor (TGF)-b signalling to co-ordinate morphogenesis, and chondrogenic and angiogenic events during skeletal development [2,101]. Perlecan also interacts with a number of matrix stabilising molecules including fibrillin-1, nidogen-1 and 2, fibulin-2, fibronectin, proline/argininerich and leucine-rich repeat protein/prolargin (PRELP), von Willebrand factor protein-A related protein (WARP) and types XIII and XVIII collagen; and cell attachment proteins such as laminin, fibronectin and thrombospondin [6,8,45,54,78,87,141] and thus also has important roles to play in matrix organisation and stabilisation.…”

Topographical variation in the distributions of versican, aggrecan and perlecan in the foetal human spine reflects their diverse functional roles in spinal development

“…Major ECM components in developmental spinal tissues include the fibrillar types I and II, VI, IX and lattice forming type X collagens as well as the large spacefilling ECM CS-rich proteoglycans aggrecan and versican (Gustafsson et al 2003;Hayes et al 2001). Perlecan (HSPG2), a HS-substituted matrix proteoglycan, is also a prominent component of the primordial cartilaginous rudiments in the developing spine and a component of small blood vessels in the looser connective tissues surrounding these structures (Arikawa-Hirasawa et al 1999;Gustafsson et al 2003;Melrose et al 2002Melrose et al , 2003Melrose et al , 2008a. A greater understanding of how these spinal components are assembled may provide valuable clues as to how to best approach their biological repair in mature tissues (Kalson et al 2008;Melrose et al 2008b;Richardson et al 2007;Zhang et al 2008).…”

Heparan Sulfate Proteoglycan Modulation of Wnt5A Signal Transduction in Metastatic Melanoma Cells

“…They mediate fibroblast growth factor, Hedgehog, epidermal growth factor, transforming growth factor-␤, and WNT signaling pathways (6 -11). HSPGs consist of two types, cell surface and basement membrane-associated HSPGs (12). Cell surface HSPGs are glycoproteins with covalently attached unbranched and modified sugar chains known as glycosaminoglycans (GAGs).…”