Vitronectin and Fetuin-A: Newfangled Glycoproteins in Periodontits and Coronary Artery Diseases: A Narrative Review

Periodontitis, an intricate inflammatory condition impacting oral support structures, is increasingly recognized as a potential contributor to systemic ailments, notably cardiovascular diseases. Its pathophysiology involves the release of inflammatory molecules like cytokines and chemokines, exacerbating conditions like atherosclerosis. Within this complex web of inflammation, glycoproteins like vitronectin and fetuin-A have emerged as pivotal players, with vitronectin's multifunctional roles in cellular processes and fetuin-A's influence on metabolic pathways. Understanding their involvement in periodontitis and cardiovascular disorders offers promise in leveraging them as diagnostic biomarkers, potentially enhancing disease management and prevention


Introduction
Periodontitis is a multifactorial inflammatory condition that impacts the soft and hard tissues that support the teeth [1].The pathophysiology of periodontitis involves the production of specific cytokines and chemokines, leading to the activation of host-derived proteinases.These proteinases play a crucial role at different stages of the disease as they are released over defined time periods [2].
Many systemic disorders, such as cardiovascular diseases, are thought to be mostly caused by inflammation [3].Chronic periodontitis initiates a systemic inflammatory response that exacerbates cardiovascular disease.These two common pathologies, periodontitis and cardiovascular disorders, can mutually intensify their adverse effects on each other's pathophysiology [4].Since its inflammatory nature has been well understood, atherosclerosis can affect the development and spread of other inflammatory diseases including periodontitis.The acute-phase response is one of the primary defence mechanisms to restore equilibrium and eliminate the toxin.Acute-phase proteins are primarily glycoproteins that exhibit a rapid increase in their serum concentration during the initial phases of an infection.This increase can be substantial, often reaching up to 100-fold higher levels, and it typically remains elevated throughout the course of the infection [5].Salivary biomarkers are utilized for diagnosing and predicting both periodontal and systemic diseases.Recently, novel glycoproteins like nline at: le o b ila Ava -261 -vitronectin and fetuin-A have been investigated for their role in periodontal and systemic inflammatory conditions such as cardiovascular diseases.
Vitronectin also known as serum-spreading factor or S-protein is one such biomarker found in the granules of blood platelets, extracellular matrix, and plasma.It is a member of the family of adhesive glycoproteins, which play a variety of roles in the body.These roles include complement activation, blood clotting, binding to proteoglycans, and matrix modification.Vitronectin regulates cell differentiation, proliferation, migration, and morphogenesis in addition to playing a critical function in securing cells to their matrix.One such cell adhesion molecule (CAM) plays a role in wound healing, where the reduction of inflammation is necessary, despite being essential for cell spreading.In directing the inflammation, it might play a pro-inflammatory role.Human atheromatous plaques contain vitronectin, which suggests that it may play a role in atherosclerosis and restenosis [6].
Fetuin-A [Alpha 2-Heremans Schmid Glycoprotein (AHSG)], is an additional cystatin superfamily member glycoprotein that is primarily produced by hepatic and adipose tissues.Fetuin-A has earned recognition as a versatile plasma agent because of its activity in the body's metabolic processes, insulin resistance, adipogenesis control, and mineralization [7].It is a negative acute phase protein that is downregulated by inflammatory mediators.It alters the expression of the atheroprotective adipokine adiponectin and decreases the uptake and storage of free fatty acids in adipocytes.Periodontitis and cardiovascular disorders are particularly interested in its role in preventing ectopic calcification, particularly in arteries, by regulating calcium and bone metabolism.Reduced fetuin-A levels brought on by prolonged periodontitis may encourage calcification and inflammation, which might increase the risk of various cardiovascular consequences [8].
Vitronectin and fetuin-A play a critical role in regulating the connection between cell adhesion and physiological proteolysis, especially in the context of bone metabolism and turnover.They are considered potent inhibitors of systemic calcification [7].
This article explores the potential action of vitronectin and fetuin-A as diagnostic biomarkers in light of their relationship to periodontitis and coronary artery diseases.

Search strategy
The articles were independently evaluated during the screening procedures in accordance with the eligibility requirements.The articles ranged from 2013 to 2023 were searched in various search engines such as PubMed, Scopus, Science Direct, Research Gate and Web of Science databases.MeSH terms used to find the articles were "Vitronectin," "Fetuin-A," "Periodontitis," "Coronary artery disease," "Inflammation" and "Glycoproteins."

Inclusion criteria
The inclusion criteria include the following: studies written in English; studies published in Pub Med, Scopus, Science Direct, Research Gate, and Web of Science; narrative reviews, research articles, and other studies.

Exclusion criteria
Case reports/series, book chapters, articles published prior to the year 2013, and articles that are not relevant to biomarkers in dentistry were excluded from the current literature survey.

Study selection
Eligibility criteria, databases, and search strategies were used to identify relevant studies.Reviewers independently evaluated the study titles and abstracts during the screening procedures, reading, analyzing, and selecting abstracts in accordance with the eligibility requirements.A total of 30 papers were retrieved during the selection process and a thorough screening of full-text articles was performed.16 were excluded, 11 were found to be out of scope, and 5 were found to have insufficient details.A total of 14 significant articles were generated.The articles underwent crucial findings and judgments in order to construct significant outcomes of vitronectin and Fetuin-A as potential biomarkers in periodontitis and coronary artery diseases.[Figure 1]

Results and Discussion
Out of the 200 files found, 28 articles showed the expression of Vitronectin and Fetuin-A in different inflammatory conditions, with 14 of them specifically focusing on the role of Vitronectin and Fetuin-A, particularly in coronary artery diseases.These articles were taken into consideration to explore the synergistic effect of both biomarkers associated with periodontal and cardiovascular studies.[Table 1 and Table 2].Inflammation is a well-orchestrated, programmed signalling defensive reaction that occurs in response to an infection and/ or an injury, initiated to protect the host tissues thereby preventing further progression of the disease, thus leading to initiation of tissue healing.Though this natural response aims to revert the tissue homeostasis, it is considered to be destructive when it turns out to be uncontrolled and hyper-responsive [4].Hence inflammation is considered as a double-edged sword where it plays both the role of protective and injurious response to the human body depending on its type and duration [3,4].
The initial inflammation in the periodontal tissues is considered a physiologic defense mechanism against the microbial challenge, which on persistence leads to the development of chronic inflammation where the pre-existing innate immune response pathways are stimulated that will activate the adaptive immune response, resulting in the influx of immune and inflammatory cells such as the neutrophils and macrophages, that release chemical substances such as the cytokines to mediate the process of inflammation [3].
In response to inflammation the higher order of various glycoproteins is expressed in bone and periodontal ligament.Vitronectin and Fetuin-A are two such secreted proteins which play a crucial role in extracellular matrix structure and organization and especially in collagen assembly and hence have shown to play a critical part in inflammatory diseases such as periodontitis and cardiovascular diseases.
Vitronectin is one such multifunctional glycoprotein of 75 kD that binds to various biological ligands.Vitronectin was discovered in 1967 and initially called S-protein, but was later renamed by Hayman EG et al.It is an important component of the human extracellular matrix (ECM), and is synthesized in the liver and secreted into plasma.Vitronectin plays a crucial role in many biological processes including cell migration, adhesion and angiogenesis [8].The interaction of vitronectin with the urokinase plasminogen activator-urokinase plasminogen activator receptor (uPA-uPAR) complex and integrin receptors is a part of the plasminogen activation system involved in old tissue degradation (pericellular proteolysis), reorganization and wound healing and is a key determinant in homeostatic processes [9].
The multifunctional human glycoprotein vitronectin plays a significant role in cell migration, tissue repair and regulation of membrane attack complex (MAC) formation.It also promotes neutrophil infiltration and, thus, enhances the inflammatory process during infection.There is a higher prevalence of coarse granular deposits of C3d, C9 and vitronectin in subepithelial tissues of patients with periodontitis.Vitronectin is involved in regulation of the terminal pathway of complement activation to nline at: le o b ila Ava -265 -limit the self-reactivity of the innate immune response.This may indicate an increased turnover of complement in gingival tissues [13].Hence complement activation is down regulated in periodontitis, at the expense of adequate local opsonic function.Vitronectin is also associated with the connective tissue of the marginal gingiva, the periodontal ligament, as well as the endosteum and periosteum with high staining intensity of vitronectin in the periodontal ligament.The concept that PDL responds to the mechanical stress produced by external forces such as orthodontic force induces a remodelling process.Various studies demonstrated that mechanical force applied to human PDL resulted in an increase in the synthesis of laminin, fibronectin and vitronectin in patients undergoing orthodontic therapy and suggested that alterations in the physical environment of cells found in the periodontium can affect biochemical processes, including those that govern the synthesis of structural macromolecules such as extra cellular matrix protein [13,14].
Vitronectin has several binding domains which interact with a variety of plasma and cell proteins and bind with multiple ligands, including the soluble vitronectin receptor in the endothelial cells.A study demonstrated that anti-vitronectin antibodies inhibit the aggregation of platelets in vitro, indicating that vitronectin plays a role in platelet accumulation at the sites of endothelial injuries.Anti-vitronectin antibody prevents the second wave of platelet aggregation in both platelet-rich plasma and gel-filtered platelets [15].Endogenous platelet vitronectin may serve to stabilize the platelet-platelet interactions when platelets are activated and platelet granule contents are released [14,15].In addition to its role in platelet interactions, vitronectin controls the thrombotic response evoked by vascular injury by regulating thrombin function.Studies have shown that vitronectin accumulated in human atherosclerotic plaques that are dependent on the vitronectin receptor-αVβ3 and αVβ5 play an important role of migration of smooth muscle cells into the intima layer which is a main contributor to intima thickening in atherosclerotic lesions [11,15].
Fetuin-A, a cysteine protease inhibitor, is part of the cystatin superfamily.It's a serum glycoprotein weighing around 51-67 kDa, initially isolated from bovine fetal serum.The human counterpart is known as α2-Heremans-Schmid glycoprotein (AHSG).It's primarily produced in the liver, with some synthesis in the kidneys, placenta, and tongue.Fetuin-A has two cystatin domains, D1 and D2, followed by a 100-residue C-terminal segment, with a total of 367 amino acids [8].
Fetuin-A has shown the ability to inhibit the release of High Mobility Group Box-1 protein (HMGB-1) by macrophages, particularly in chronic inflammation.Moreover, its high abundance in bone, comprising 25% of non-collagenous proteins, indicates its role in mineralization.An in-vitro study demonstrated the role of fetuin-A in inhibiting the precipitation of hydroxyapatite from solutions supersaturated with calcium and phosphate by the subsequent formation of the fetuin-mineral complex.Hence it is suggested that fetuin inhibits phase separation in serum and modulates apatite formation during mineralization [10].
The protective function of fetuin-A has also been shown to have a cardio protective effect against cardiovascular diseases.First, fetuin-A can inhibit coronary artery calcification (CAC), which is a central characteristic of atherosclerotic cardiovascular disease, by increasing the blood solubility of calcium and phosphorus and preventing spontaneous mineral precipitation in the vasculature [12].In addition to its role as a systemic calcification inhibitor, fetuin-A serves as a multifaceted protective factor.It counters local calcification, influences macrophage polarization, and reduces inflammation and fibrosis [18].Fetuin-A has also been shown to have an effect on various pro-inflammatory cytokines in periodontal disease by down-regulation of several pro-inflammatory molecules, including tumor necrosis factor-α, interleukin-6, and interferon-γ.These cytokines are induced by periodontal inflammation and affect periodontitis pathogenesis.By regulating transforming growth factor and bone morphogenic protein, fetuin-A has potent osteogenic and differentiation effects and low serum fetuin-A level is correlated with worse periodontal status and could thus potentially serve as a marker of periodontitis [20].
Fetuin-A can be influenced by matrix metalloproteinases (MMPs), which play important roles in bone and periodontal diseases.Particularly, MMP-7, and to some extent, MMP-3, impact fetuin's ability to inhibit hydroxyapatite formation by cleaving it.This suggests that increased MMP levels in inflammatory diseases may disrupt mineralization regulation by fetuin-A, potentially elevating the risk of conditions like periodontitis [16,20].Fetuin appears to be a strong inhibitor of calcium-phosphate precipitation and calcification.Patients with dental calculus showed higher levels of GCF and saliva fetuin-A, possibly because the protein leaked from serum to inhibit calculus.Another reason for elevated fetuin-A in GCF and saliva could be its strong affinity for hydroxyapatite, the primary mineral in dental calculus.This suggests that fetuin-A levels increase in local circulations like GCF and saliva to prevent dental calculus formation [

Figure 1 :
Figure 1: PRISMA flow diagram of articles screening and selection.

Table 1 :
Animal studies related to vitronectin and fetuin-A as biomarkers in periodontitis and coronary artery disease.
[11]ulation of fetuin-A gene expression in the neonatal pig liver.Ramsay TG et al.,[10]Animal study (In vitro study)Hepatocyte experiments indicate that multiple hormones and cytokines play a role in regulating fetuin-A during the early growth of pigs.3NovelVitronectinVariations and Their Comparative Analysis in Six Porcine Breeds.Yan W et al.,[11]Animal study (In vitro study)Porcine vitronectin gene was polymorphic and appears to have different genetic characteristics at vitronectin among six breeds.nline at:

Table 2 :
Human studies related to vitronectin and fetuin -A as biomarkers in periodontitis and coronary artery disease.