Absence of αvβ6 Integrin Is Linked to Initiation and Progression of Periodontal Disease

Abstract

Integrin ␣v␤6 is generally not expressed in adult epithelia but is induced in wound healing, cancer, and certain fibrotic disorders. Despite this generalized absence, we observed that ␣v␤6 integrin is constitutively expressed in the healthy junctional epithelium linking the gingiva to tooth enamel. Moreover, expression of ␣v␤6 integrin was down-regulated in human periodontal disease, a common medical condition causing tooth loss and also contributing to the development of cardiovascular diseases by increasing the total systemic inflammatory burden. Remarkably, integrin ␤6 knockout mice developed classic signs of spontaneous, chronic periodontal disease with characteristic inflammation, epithelial down-growth, pocket formation, and bone loss around the teeth. Integrin ␣v␤6 acts as a major activator of transforming growth factor-␤1 (TGF-␤1), a key anti-inflammatory regulator in the immune system. Co-expression of TGF-␤1 and ␣v␤6 integrin was observed in the healthy junctional epithelium. Moreover, an antibody that blocks ␣v␤6 integrin-mediated activation of TGF-␤1 initiated inflammatory periodontal disease in a rat model of gingival inflammation. Thus, ␣v␤6 integrin is constitutively expressed in the epithelium sealing the gingiva to the tooth and plays a central role in protection against inflammatory periodontal disease through activation of TGF-␤1. (Am J Pathol

Epithelial Integrins with Special Reference to Oral Epithelia

“…Curiously, 2 proteins that are not commonly found in other epithelial basement membranes, namely, type VIII collagen and versican, have also been reported to be present at the JE-tooth interface (Salonen et al, 1991;Abiko et al, 2001). In addition, other proteins may also be present, such as tenascin-C (Ghannad et al, 2008). Likely more proteins will be found with emerging proteomics techniques.…”

Critical role for αvβ6 integrin in enamel biomineralization

“…This integrinmediated activation plays an important anti-inflammatory role in vivo , as it regulates experimental TGF-b1-dependent fibrosis in various organs (Hahm et al, 2007;Horan et al, 2008;Patsenker et al, 2008). Furthermore, avb6 integrin is expressed in junctional epithelial cells that mediate gingival soft tissue adhesion to tooth enamel (Ghannad et al, 2008). Interestingly, loss of b6 integrin in mice is associated with characteristics of human periodontal disease, suggesting that avb6 integrin plays a role in protecting periodontal tissues from inflammatory changes leading to periodontal disease (Ghannad et al, 2008).…”

“…Furthermore, avb6 integrin is expressed in junctional epithelial cells that mediate gingival soft tissue adhesion to tooth enamel (Ghannad et al, 2008). Interestingly, loss of b6 integrin in mice is associated with characteristics of human periodontal disease, suggesting that avb6 integrin plays a role in protecting periodontal tissues from inflammatory changes leading to periodontal disease (Ghannad et al, 2008). Junctional epithelium is derived from cells arising from the reduced enamel epithelium during tooth eruption (Schroeder and Listgarten, 1977).…”

Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability

“…17 Lack of ITGB6, therefore, results in enhanced inflammatory response. In knockout mice, degenerating hair follicles were surrounded by foci of mononuclear cells 15 and inflammatory infiltrates were enhanced in gingiva and lung, 14,16 but not in other epithelial tissues. 17 While TGFβ-1 downregulation facilitates faster re-epithelialization post injury and protects against fibrosis, 18 chronic lack of TGFβ-1 leads to failure of tissue regeneration resulting in epidermal hypoproliferation, blocked hair follicle growth and neurodegeneration in brain.…”

“…ITGB6 variants were previously shown to cause amelogenesis imperfecta (AI) in young children, 11,12 and Itgb6-knockout mice present with enamel defects, 13 periodontal disease 14 and juvenile baldness. 15 The occurrence of AI in knockout mice and in children o10 years old was supported by enamel defects seen by electron microscopy.…”