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Perlecan in Pericellular Mechanosensory Cell-Matrix Communication, Extracellular Matrix Stabilisation and Mechanoregulation of Load-Bearing Connective Tissues

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Perlecan in Pericellular Mechanosensory Cell-Matrix Communication, Extracellular Matrix Stabilisation and Mechanoregulation of Load-Bearing Connective Tissues International Journal of Molecular Sciences Review Perlecan in Pericellular Mechanosensory Cell-Matrix Communication, Extracellular Matrix Stabilisation and Mechanoregulation of Load-Bearing Connective Tissues Farshid Guilak 1,2 , Anthony J. Hayes 3 and James Melrose 4,5,6,* 1 Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA; [email protected] 2 Shriners Hospitals for Children—St. Louis, St. Louis, MO 63110, USA 3 Bioimaging Research Hub, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales CF10 3AX, UK; [email protected] 4 Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia 5 Raymond Purves Laboratory, Institute of Bone and Joint Research, Kolling Institute, Northern Sydney Local Health District, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia 6 Sydney Medical School, Northern, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia * Correspondence: [email protected] Abstract: In this study, we review mechanoregulatory roles for perlecan in load-bearing connective tissues. Perlecan facilitates the co-acervation of tropoelastin and assembly of elastic microfibrils in translamellar cross-bridges which, together with fibrillin and elastin stabilise the extracellular matrix of the intervertebral disc annulus fibrosus. Pericellular perlecan interacts with collagen VI and XI to define and stabilize this matrix compartment which has a strategic position facilitating two-way cell-matrix communication between the cell and its wider extracellular matrix. Cues from Citation: Guilak, F.; Hayes, A.J.; the extracellular matrix are fed through this pericellular matrix back to the chondrocyte, allowing it Melrose, J. Perlecan in Pericellular to perceive and respond to subtle microenvironmental changes to regulate tissue homeostasis. Thus Mechanosensory Cell-Matrix Communication, Extracellular Matrix perlecan plays a key regulatory role in chondrocyte metabolism, and in chondrocyte differentiation. Stabilisation and Mechanoregulation Perlecan acts as a transport proteoglycan carrying poorly soluble, lipid-modified proteins such as the of Load-Bearing Connective Tissues. Wnt or Hedgehog families facilitating the establishment of morphogen gradients that drive tissue Int. J. Mol. Sci. 2021, 22, 2716. morphogenesis. Cell surface perlecan on endothelial cells or osteocytes acts as a flow sensor in blood https://doi.org/10.3390/ijms22052716 and the lacunar canalicular fluid providing feedback cues to smooth muscle cells regulating vascular tone and blood pressure, and the regulation of bone metabolism by osteocytes highlighting perlecan’s Academic Editor: Eok-Soo Oh multifaceted roles in load-bearing connective tissues. Received: 30 January 2021 Keywords: perlecan: mechanosensation; elastin; fibrillin; PCM stabilization; tissue homeostasis; IVD Accepted: 5 March 2021 biomechanics; mechanobiology; type VI collagen; meniscus Published: 8 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- 1.1. Perlecan is a Modular Proteoglycan iations. Perlecan is a large modular, multifunctional heparan sulphate (HS) proteoglycan (HS- PG) that is abundant in vascularized tissues but also occurs in poorly and non-vascularized connective tissues such as articular cartilage, intervertebral disc (IVD), meniscus, liga- Copyright: © 2021 by the authors. ment and in tendon as a hybrid form, where at least one of its HS glycosaminoglycan Licensee MDPI, Basel, Switzerland. (GAG) chains is replaced by a chondroitin sulphate (CS) chain [1,2] (Figure1a). Smooth This article is an open access article muscle cells (SMCs) synthesize a CS/HS hybrid form of perlecan whereas keratinocytes distributed under the terms and in epithelial tissues synthesize a form containing CS, HS and keratan sulphate (KS) [3], conditions of the Creative Commons and endothelial cell perlecan is mono-substituted with HS. Mast cells synthesize perlecan Attribution (CC BY) license (https:// species with smaller molecular weight core proteins [4] apparently arising from alternative creativecommons.org/licenses/by/ splicing and/or protease cleavages in the immunoglobulin-rich domain IV, thus generating 4.0/). Int. J. Mol. Sci. 2021, 22, 2716. https://doi.org/10.3390/ijms22052716 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 20 Int. J. Mol. Sci. 2021, 22, 2716 2 of 20 thesize perlecan species with smaller molecular weight core proteins [4] apparently aris- ing from alternative splicing and/or protease cleavages in the immunoglobulin-rich do- mainN and IV, C thus terminal generating perlecan N and fragments C terminal of variable perlecan size. fragments Some ofof thesevariable fragments size. Some act of as thesefunctional fragments PGs in act their as functional own right PGs [5]. in their own right [5]. FigureFigure 1. 1. SchematicSchematic of the perlecan andand itsits fivefive modular modular domains domains (a ().a). and and their their interactive interactive ligands ligands (b ). (b). 1.2. Perlecan’s Participation in Physiological Processes 1.2. Perlecan’sPerlecan Participation also has important in Physiological regulatory Processes roles in many physiological processes. Perlecan on endothelial cells in the lumen of blood vessels acts as a dynamic flow sensor [6] with Perlecan also has important regulatory roles in many physiological processes. Per- detected shear forces regulating endothelial membrane polarization, cell proliferation, lecan on endothelial cells in the lumen of blood vessels acts as a dynamic flow sensor [6] cytoskeletal organization and gene expression [7]. Furthermore, this is coupled with with detected shear forces regulating endothelial membrane polarization, cell prolifera- stimulatory biophysical forces that promote cell differentiation and tissue development [8]. tion, cytoskeletal organization and gene expression [7]. Furthermore, this is coupled with Calcium signalling through transient receptor potential (TRP) channels in endothelial cells stimulatory biophysical forces that promote cell differentiation and tissue development drives vasculogenic processes [9]. TRP channels also regulate the contractile properties of [8]. Calcium signalling through transient receptor potential (TRP) channels in endothelial SMCs to regulate vasodilation and blood pressure [10]. Perlecan, is a mechanical biosensor cellsin bone, drives detecting vasculogenic external processes loading [9]. through TRP ch theannels identification also regulate of solute the contractile movement proper- in the tieslacuno-canalicular of SMCs to regulate space vasodilation of the bone matrix and blood [11–13 pressure]. [10]. Perlecan, is a mechanical biosensor in bone, detecting external loading through the identification of solute move- ment1.3. The in the Role lacuno-canalicular of Perlecan in Chondrocyte space of Mechanotransduction the bone matrix [11–13]. Mechanotransduction—the conversion of a mechanical signal to an intracellular 1.3.response—is The Role of a Perlecan crucial processin Chondrocyte in the homeostaticMechanotransduction maintenance of connective tissues such as cartilage.Mechanotransduction—the Deformation of cartilaginous conversion tissues of a me duringchanical normal signal daily to an activities intracellular exposes re- sponse—isthe chondrocytes a crucial to process varying in stresses, the homeostatic strains, hydrostatic maintenance pressure, of connective interstitial tissues fluid such flow, as cartilage.electrokinetic Deformation effects and of cartilaginous ionic changes tissues that alter during the normal local osmotic daily activities pressure exposes [14]. Com- the chondrocytespression of the to varying cartilage stresses, matrix strains, causes waterhydrostatic to be pressure, exuded frominterstitial the tissue, fluid flow, while elec- the trokineticnegatively effects charged and proteoglycansionic changes that (PGs) alter are the retained local osmotic and attract pressure positive [14]. Compression counter-ions. ofThis the phenomenon cartilage matrix results causes in fluctuationswater to be inexuded the interstitial from the osmolaritytissue, while of the the negatively ECM and chargedpericellular proteoglycans matrix (PCM) (PGs) [15 are,16] retained which can and influence attract positive the physiologic counter-ions. activity This of phenom- the chon- enondrocyte results [17,18 in]. fluctuations In the last ten in years,the interstitial several ion osmolarity channels, of pumps the ECM or exchangers and pericellular have beenma- trixidentified (PCM) in[15,16] the cell which membrane can influence of chondrocytes the physiologic and shown activity to of have the importantchondrocyte regulatory [17,18]. Inroles the [last19–25 ten]. Foryears, example, several theion electrogenicchannels, pumps Na+ /K+pumpor exchangers regulates have been Na+, identified K+ -ATPase in theand cell the membrane resting potential of chondrocytes of the chondrocyte and shown [ 21to ].have Electrochemical important regulatory gradients roles of Na+ [19–25]. and ForK+ areexample, established the electrogenic and maintained Na+ /K+pump by this active regulates ATP-requiring Na+, K+ -ATPase pump [ 26and,27 ].the The resting pres- potentialence of Na+/K+, of the chondrocyte pump proteins [21]. Electrochemi in the chondrocytecal gradients cell membrane of Na+ and have K+ beenare established identified andusing maintained immunological
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