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The Importance of Wnt Pathways for Bone Metabolism and Their Regulation by Implant Topography C

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The Importance of Wnt Pathways for Bone Metabolism and Their Regulation by Implant Topography C EuropeanC Galli et Cells al. and Materials Vol. 24 2012 (pages 46-59) DOI: 10.22203/eCM.v024a04 Regulation of WNT signalling by ISSNimplant 1473-2262 surfaces THE IMPORTANCE OF WNT PATHWAYS FOR BONE METABOLISM AND THEIR REGULATION BY IMPLANT TOPOGRAPHY C. Galli1,2,*, M. Piemontese3, S. Lumetti1, E. Manfredi1, G.M. Macaluso1 and G. Passeri2 1Sez. Odontostomatologia, 2Dept. Internal Medicine and Biomedical School, 3Dept. Experimental Medicine, University of Parma, Parma, Italy Abstract Introduction Endosseous implants are important tools to replace Titanium endosseous implants are a versatile tool in missing teeth or damaged tissue segments. Their clinical medicine, with broad applications both in dentistry, where success depends on their integration in bone and, thus, they are commonly used to support dental prosthesis, on the response of bone cells to material and surface and orthopaedics, to replace damaged bone segments. characteristics. Recent evidence has shown that surface The proper clinical function of an implant requires topography and chemistry affect WNT signalling, a pivotal the formation of sound bone in close contact with the pathway for the commitment of mesenchymal progenitors implant body, a process that is generally referred to as to the osteoblast lineage and for bone homeostasis. WNT osseointegration (Brånemark, 1983; van Steenberghe et signalling comprises several cascades that, acting through al., 1991). Mesenchymal cells and osteoblasts in particular, different effectors, modulate several aspects of cell are the main players in this process, because they deposit behaviour. the newly formed bone that will encase the implant. Their It has been shown that cells growing on rough titanium initial attachment, adhesion, and their response to implants surfaces display a different expression profile for WNT are therefore critical determinants to the subsequent tissue factors, and that surface features can alter the response reaction (Anselme et al., 2010; Anselme, 2011). All these of bone cells to WNT factors. Although the underlying events can be affected by the physical and chemical mechanisms to this regulation are still poorly understood, features of the substrate, such as its chemical composition, the present review reports intriguing evidence that that wettability, and topography, which can, in turn, affect the cell cytoskeletal signalling is involved in activating WNT pattern of protein adsorption on the biomaterial surface. signalling in cells growing on rough implant surfaces. Several authors have shown that surface characteristics can alter cell growth and differentiation, the expression of Keywords: Topography; WNT; titanium implants; extracellular matrix components and their mineralisation osteoblasts; cytoskeleton. both in vitro (Keller et al., 2003; Schneider et al., 2003; Lossdorfer et al., 2004; Masaki et al., 2005; Arcelli et al., 2007; Wall et al., 2009; Liu et al., 2010; Wennerberg and Albrektsson, 2010; Donos et al., 2011a; Liu et al., 2012) and in vivo (Buser et al., 2004; Germanier et al., 2006; Gahlert et al., 2007; Bornstein et al., 2008; Coelho et al., 2011; Donos et al., 2011b; Ivanovski et al., 2011; Park, 2011; Kämmerer et al., 2012). The optimal implant characteristics to ameliorate their integration in bone, including roughness and texture, are however still the object of intense debate. To this purpose, a deeper understanding of the molecular pathways involved in osteoblast differentiation may prove decisive. Recently, the role of WNT signalling in bone formation has been elucidated, and it appears as a fundamental signalling cascade for osteoblast differentiation and bone formation. Recent evidence suggests that these complex pathways may also play a role in surface-induced osteoblast differentiation, and they could represent useful therapeutic targets to improve the clinical performance of endosseous *Address for correspondence: implants. The aim of this review is therefore to examine Carlo Galli the available evidence about the role of WNT signalling Sez. Odontostomatologia in bone formation and its regulation by implant surfaces. University of Parma Via Gramsci 14, 43100 Parma, Italy WNT signalling Telephone Number:+39 0521 986722 FAX Number: +39 0521 292955 WNT signalling is activated by specific secreted 350-400 E-mail: [email protected] amino acid long lipid-modified proteins (Cadigan and www.ecmjournal.org 46 C Galli et al. Regulation of WNT signalling by implant surfaces Fig. 1. Diagram showing the main molecular events during WNT canonical signalling. Cytoskeletal β-catenin is phosphorylated by a multimolecular complex and undergoes Ubiquitin (Ub) mediated degradation. Upon binding of specific WNT factors to a Frizzled-LRP receptor complex, the destruction complex is inhibited, thus allowing β-catenin to translocate to the nucleus and bind TCF/Lef. Nusse, 1997; Katoh and Katoh, 2005). They are known to stabilisation (Kishida et al., 1999), while the PDZ and bind to a receptor complex comprising the Frizzled (Fzd) DEP domains are required for activation of WNT non- receptor (van Amerongen et al., 2008; Angers and Moon, canonical cascades. In the absence of WNT stimulation, 2009) and co-receptors that determine the activation of β-catenin is retained in the cytoplasm by a multi-protein specific effectors (Mikels and Nusse, 2006). This results degradation complex comprising Glycogen synthase kinase in the activation of several different molecular pathways: 3 (GSK3) (Force and Woodgett, 2009) and Casein kinase the WNT canonical pathway, which requires β-catenin 1a (CKI) (Bernatik et al., 2011), and two scaffold proteins, (Fig. 1), and a number of so-called non-canonical WNT Adenomatous polyposis coli (APC) (Tanneberger et al., pathways, among which the Planar Cell Polarity (PCP) 2011) and Axin (Chia and Costantini, 2005). This leads pathway and the Ca2+-dependent pathway are the best to β-catenin phosphorylation and its subsequent targeting known (Fig. 2A,B). for proteosomal degradation (Clevers, 2006; Verheyen and Gottardi, 2010). WNT canonical pathway β-catenin is a multirole protein that can act both as a The canonical or WNT/β-catenin pathway requires normal constituent of cell-to-cell junctions by associating binding of members of the WNT1 class (WNT1, WNT3, to membrane cadherins and as a co-transcription factor. It WNT3a, WNT7a, WNT7b, WNT8a) to Fzd and a contains a central domain of 12 Armadillo repeats, which member of the low-density lipoprotein receptor related mediate most of the interactions of β-catenin with other protein family, LRP5/6 (Mikels and Nusse, 2006; van proteins (Xu and Kimelman, 2007; Angers and Moon, Amerongen and Nusse, 2009). This recruits Disheveled 2009). Upon receptor activation, Frz binds to Dvl and (Dvl) to the cell membrane and activates it (Lee et al., the PPPS/TP motifs of LRP are phosphorylated, thus 2008; Turm et al., 2010). Dvl consists of three molecular recruiting Axin and inhibiting GSK3 activity and the domains: the N-terminal DIX domain, a central PDZ formation of the destruction complex. Recent evidence domain, and a C-terminal DEP domain (Axelrod et al., has demonstrated that LRPs can also be phosphorylated 1998; Boutros and Mlodzik, 1999; Wharton, 2003; Pan through an alternative, MAPK-dependent mechanism et al., 2004). Dvl is considered to play a pivotal role in (Cervenka et al., 2011). These events cause the release of regulating WNT-activated signalling cascades. It has been β-catenin, which then can translocate to the nucleus, where shown that the DIX and PDZ domains trigger β-catenin it interacts with a member of the T cell factor/lymphoid www.ecmjournal.org 47 C Galli et al. Regulation of WNT signalling by implant surfaces Fig. 2. Diagram summarising the non canonical Planar Cell Polarity (left panel) and Calcium-dependent (right panel) WNT signalling pathways. Both pathways activate Dishevelled (Dvl) but do not require β-catenin involvement, relying on direct activation of effectors controlling cytoskeletal rearrangement (PCP pathway) or Ca2+-Calmodulin activation. enhancer factor (TCF/Lef1) transcription factor family factors, such as WNT5a, to a Fzd/orphan tyrosine kinase (Mosimann et al., 2009), of which several members have Ror2 receptor complex (Mikels and Nusse, 2006) (Fig. been identified (Arce et al., 2006; Hoeppner et al., 2009). 2A). The PCP pathway activates downstream effector The binding of the first 50 amino acids of TCFs and the molecules small GTPases RhoA, Rac1 and Cdc42, which 3-10 Armadillo repeats of β-catenin dramatically increases have several roles in cell physiology (Schlessinger et al., TCF/Lef1 affinity for DNA and induces the recruitment of 2009), through Dvl. other transcriptional co-activators, such as p300 and cAMP Dvl interacts with Daam1 through its PDZ and DEP response element-binding protein (p300/CBP), which domains (Gao and Chen, 2010), and they together interact synergistically regulate the expression of canonical WNT with the Rho guanine nucleotide exchange factor (GEF), target genes (Tutter et al., 2001; Mosimann et al., 2009). thus inducing the formation of a RhoA-GTP complex, which, in turn, activates ROCK kinase. This pathway has WNT non-canonical pathways been shown to control actomyosin-induced tensional forces Some Wnt factors can activate downstream signalling within the cytoskeleton and thus the reorganisation and independently of β-catenin, which are collectively known rearrangement of the cytoskeleton (Gao and Chen, 2010). as non-canonical pathways. Two signalling
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