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Shedding New Light on the Role of 3 and 51 Integrins in Rheumatoid

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Shedding New Light on the Role of 3 and 51 Integrins in Rheumatoid molecules Review Shedding New Light on The Role of ανβ3 and α5β1 Integrins in Rheumatoid Arthritis 1, 1, 1, 1,2, Arwa Morshed y, Abdul Baset Abbas y , Jialiang Hu * and Hanmei Xu * 1 The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing 210009, China; [email protected] (A.M.); [email protected] (A.B.A.) 2 Nanjing Anji Biotechnology Co. Ltd., Nanjing 210046, China * Correspondence: [email protected] (J.H.); [email protected] (H.X.) These authors contributed equally to this work. y Received: 12 March 2019; Accepted: 18 April 2019; Published: 18 April 2019 Abstract: ανβ3 and α5β1 are essential glycoproteins involved in the pathogenesis of rheumatoid arthritis (RA). Understanding of the role these integrins play in disease have been analyzed via description of cells-expressing ανβ3 and α5β1 and their mediators to trigger inflammation. ανβ3 and α5β1 facilitate cells-ECM and cell-cell communication, producing pro-inflammatory factors. Pro-inflammatory factors are essential for the building of undesirable new blood vessels termed angiogenesis which can further lead to destruction of bones and joints. Despite many attempts to target these glycoproteins, there are still some problems, therefore, there is still interest in understanding the synergistic role these integrins play in the pathogenesis of RA. The purpose of this review is to gain insights into the biological effects of ανβ3 and α5β1 in synovial tissues that are relevant to pathogenesis and therapy of RA. Keywords: integrin; αvβ3; α5β1; rheumatoid arthritis; angiogenesis; antagonist 1. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease with joints inflammation associated with synovitis, pannus formation and cartilage damage [1]. It involves extreme progressive bone resorption that often ultimately results in articular bone erosion and periarticular bone demineralization [2]. These conditions can impair other non-joint body systems such as chest, nerves, skin and eyes [3]. Moreover, it can also affect blood vessels and other important organs, including the liver and spleen [4]. Synoviocytes and infiltrated immune cells mediate immune response disorders in RA [5]. Nevertheless, the mechanistic basis of RA pathogenesis has not been fully elucidated. Insight into the molecular pathogenic mechanisms must still be understood. Integrins occur within RA pathogenesis and facilitate extracellular protein communication and inflammation of synovial cells, resulting in pathological intracellular signaling mediators. Additionally, integrins encourage cellular feedback through inflammation, osteoporosis, angiogenesis and apoptosis resistance by regulating cell proliferation and migration [6,7]. Integrins are heterodimeric adhesion glycoproteins that serve as signaling receptors. These heterodimeric structures consist of two different subunits, an α subunit and a β subunit. α/β subunits have particular extracellular matrix (ECM) protein binding sites to regulate essential cellular survival, motility, migration, inflamed responses and invasion [8]. There are eighteen α subunits and eight β subunits. These subunits together form twenty-four integrin molecules [9]. Based on the variety of ligands, integrins often can be classified into two groups as illustrated in Figure1. Arg-Gly-Asp (RGD) binding receptors and non-RGD binding receptors. RGD receptors comprise α5β1, Molecules 2019, 24, 1537; doi:10.3390/molecules24081537 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 15 motility, migration, inflamed responses and invasion [8]. There are eighteen α subunits and eight β subunits. These subunits together form twenty-four integrin molecules [9]. Based on the variety of ligands,Molecules 2019integrins, 24, 1537 often can be classified into two groups as illustrated in Figure 1. Arg-Gly-Asp2 of 14 (RGD) binding receptors and non-RGD binding receptors. RGD receptors comprise α5β1, α8β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, and αllbβ3. Non-RGD receptors are subdivided into three categories; α8β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, and αllbβ3. Non-RGD receptors are subdivided into three non-RGD binding collagen receptors: α1β1, α2β1, α10β1 and α11β1, non-RGD laminin receptors: categories; non-RGD binding collagen receptors: α1β1, α2β1, α10β1 and α11β1, non-RGD laminin α3β1, α6β1, α6β4 and α7β1 and non-RGD leukocyte receptors: αEβ7, α4β1, α4β7, α9β1, αDβ2, αLβ2, receptors: α3β1, α6β1, α6β4 and α7β1 and non-RGD leukocyte receptors: αEβ7, α4β1, α4β7, α9β1, αMβ2 and αXβ2 [10,11]. αDβ2, αLβ2, αMβ2 and αXβ2 [10,11]. FigureFigure 1. 1. ClassificationClassification of of integrins. integrins. Integrins Integrins are are di dividedvided into into RGD RGD binding binding receptors receptors and and non-RGD non-RGD bindingbinding receptors. receptors. RGD RGD binding binding receptors receptors include αvβ1,1, αvβ3,3, ααvvββ5,5, ααvvββ6,6, ααvvββ8,8, ααllbllbββ3,3, αα55ββ11 and and αα88ββ1.1. Non-RGD Non-RGD binding binding receptors receptors include include collagen collagen binding binding receptors receptors ( (α11ββ1,1, αα22ββ1,1, αα1010ββ11 and and αα1111ββ1),1), lamininlaminin binding binding receptors receptors ( (αα33ββ1,1, αα66ββ1,1, αα66ββ44 and and αα77ββ1)1) and and leukocyte leukocyte binding binding receptors receptors ( (ααEEββ7,7, αα44ββ1,1, αα44ββ7,7, αα99ββ1,1, ααDDββ2,2, ααLLβ2,β2, αMαMβ2β and2 and αXαβX2).β2). IntegrinsIntegrins participate participate in in the the immune immune response response against against infection infection and and autoimmune autoimmune diseases. diseases. Many Many integrinsintegrins areare expressedexpressed in monocytes,in monocytes, neutrophils, neutrophils, T cells, T B cells, naturalB cells, killer natural (NK) cells,killer macrophages,(NK) cells, α β α β macrophages,dendritic cells dendritic and platelets. cells and The platelets. roles The of rolesv 3 andof αvβ53 and1 in α5 immunityβ1 in immunity are revealed are revealed by their by theircontribution contribution to immune to immune cell cell migration migration and and cell-cell cell-cell interactions interactions to to induceinduce anan efficient efficient immune immune response.response. Accumulation ofof evidence evidence from from human human and mouseand mouse models models experiments experiments have been have confirmed been α β α β confirmedand indicated and thatindicated defects that in defectsv 3 and in α5vβ13 integrin and α5 expressionβ1 integrin orexpression activation or in activation the immune in cellsthe immuneresult in cells serious result immunodeficiency in serious immunodeficiency or autoimmune or diseasesautoimmune [12,13 diseases]. [12,13]. Despite the fact that the majority of integrins have been implicated in the pathophysiology of RA, we willDespite only the focus fact on that fibronectin the majority receptors, of integrinsαvβ3 andhaveα 5beenβ1. Theimplicated functional in the homology pathophysiology of αvβ3 and of RA,α5β we1 have will been only reportedfocus on through fibronectin their receptors, coordination αvβ and3 and cooperation. α5β1. The functional The presence homology of both integrinsof αvβ3 andplays α5 anβ1 integralhave been part reported in regulating through myosin their IIcoordinati activationon inand substrate cooperation. rigidity The sensing presence and of cellular both integrinsmigration plays signaling. an integralαvβ3 part and inα 5regulatingβ1 are un-separated myosin II activation supportive in molecules substrate ofrigidity traction sensing forces and and cellularactin cytoskeleton migration signaling. remodeling αv asβ3 aand response α5β1 are to cyclicun-separated stretching supportive and stiffening molecules of ECM. of traction The complete forces andabsence actin ofcytoskeletonα5β1 can be remodeling compensated as a by response expression to cyclic of αv stretchingβ3 [14]. Furthermore, and stiffeningα vofβ 3ECM. and αThe5β1 completerepresent absence a coordinated of α5β1 system can be forcompensated the function by ofexpression each other. of α Theyvβ3 [14]. regulate Furthermore, signal transduction αvβ3 and αof5β cell1 represent signaling a coordinated cascade. Engagement system for the of αfunction5β1 causes of each calmodulin-dependent other. They regulate signal kinase transduction II (CAMKII) ofactivation cell signaling that is cascade. a mediator Engagement of α5β1 cells of migration,α5β1 causes but calmodulin-dependent ligation of αvβ3 inhibits kinase CAMKII II (CAMKII) activation activationto block α that5β1-influenced is a mediator migration of α5β1 cells [15]. migration, Moreover, butα5β ligation1 reinforces of αvinβ3 vivo inhibitsand CAMKIIin vitro endothelial activation tocells block migration α5β1-influenced during angiogenesis migration [15]. by α Moreover,vβ3 [16]. α5β1 reinforces in vivo and in vitro endothelial cells migrationInterestingly, duringαv βangiogenesis3 and α5β1 by are αv highlyβ3 [16]. expressed in an inflammatory environment [17]. Upon inflammation, fibroblasts highly express αvβ3 or α5β1, thus is accompanied by increase Interestingly, αvβ3 and α5β1 are highly expressed in an inflammatory environment [17]. Upon pro-inflammatory mediators secretion such as matrix metalloproteinases (MMPs) and osteoclast inflammation, fibroblasts highly express αvβ3 or α5β1, thus is accompanied by increase pro- activator, receptor activator of NF-κB ligand (RANKL) [18]. Moreover, fibroblast α5β1 ligation inflammatory mediators secretion such as matrix metalloproteinases (MMPs) and osteoclast increases
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