Matrix Metalloproteinases in the Periodontium-Vital in Tissue Turnover and Unfortunate in Periodontitis

Abstract

The extracellular matrix (ECM) is a complex non-cellular three-dimensional macromolecular network present within all tissues and organs, forming the foundation on which cells sit, and composed of proteins (such as collagen), glycosaminoglycans, proteoglycans, minerals, and water. The ECM provides a fundamental framework for the cellular constituents of tissue and biochemical support to surrounding cells. The ECM is a highly dynamic structure that is constantly being remodeled. Matrix metalloproteinases (MMPs) are among the most important proteolytic enzymes of the ECM and are capable of degrading all ECM molecules. MMPs play a relevant role in physiological as well as pathological processes; MMPs participate in embryogenesis, morphogenesis, wound healing, and tissue remodeling, and therefore, their impaired activity may result in several problems. MMP activity is also associated with chronic inflammation, tissue breakdown, fibrosis, and cancer invasion and metastasis. The periodontium is a unique anatomical site, composed of a variety of connective tissues, created by the ECM. During periodontitis, a chronic inflammation affecting the periodontium, increased presence and activity of MMPs is observed, resulting in irreversible losses of periodontal tissues. MMP expression and activity may be controlled in various ways, one of which is the inhibition of their activity by an endogenous group of tissue inhibitors of metalloproteinases (TIMPs), as well as reversion-inducing cysteine-rich protein with Kazal motifs (RECK).

Keywords: extracellular matrix; matrix metalloproteinases; periodontal diseases; periodontitis.

Figure 1

Schematic illustration of the basement membrane zones of epithelium. Description in the text. Created with BioRender.com.

Figure 2

A schematic domain structure of MMPs. Abbreviations: (H₂N–)—amino-terminus, SP—signal peptide, PRO—prodomain, purple vertical line—cleavage site, Cys—cysteine residue, CAT—catalytic domain, (–S–)—cysteine switch, Zn²⁺—zinc binding site, hinge—linker peptide, PEX—hemopexin-like domain, and (–COOH)—carboxyl-terminus. Created withBioRender.com.

Figure 3

A schematic summary of MMPs’ role in the development and diseases of the oral cavity. MMPs are implicated in overall oral development (1) and wound healing like dental alveolus healing after tooth extraction (2). MMPs play a role in pathological processes, substantially contributing to the development of dental erosion, dental caries, pulpitis (3), periapical periodontitis (4), periodontitis (5), and oral lesions like lichen planus or squamous cell carcinoma (6). Created with BioRender.com.

Figure 4

A schematic representation of the healthy periodontium. Abbreviations: 1. tissues: B—alveolar crest/bone, C—cementum, D—dentine, E—enamel, JE—junctional epithelium, SE—sulcular epithelium, OGE—oral gingival epithelium, GLP—gingival lamina propria, PDL—periodontal ligament, and V—blood vessel; 2. cells: MΦ—macrophage, MC—monocyte, MAST—mastocyte, PMN—polymorphonuclear leukocyte (granulocyte), (a)FB—(activated) fibroblast, NK—natural killer cell, L—lymphocyte, OB—osteoblast, OK—osteoclast, OC—osteocyte, CB—cementoblast, and CC—cementocyte; 3. GF—gingival fibers. Created with BioRender.com.

Figure 5

A schematic representation of the inflamed periodontium (periodontitis). Abbreviations: 1. tissues: B—alveolar crest (bone), C—cementum, D—dentine, DP—dental plaque, E—enamel, JE—junctional epithelium, SE—sulcular epithelium, OGE—oral gingival epithelium, GLP—gingival lamina propria, PDL—periodontal ligament, and V—blood vessel; 2. cells: DC—dendritic cell, #—CD4 T-cell and dendritic cell interaction (antigen presentation), MΦ—macrophage, MC—monocyte, MAST—mastocyte, PMN—polymorphonuclear leukocyte (granulocyte), FB—fibroblast, NK—natural killer cell, TC—T-cell, OB—osteoblast, OK—osteoclast, OC—osteocyte, CB—cementoblast, CC—cementocyte, PC—plasma cell, KC—keratinocyte, and PP—periodontal pathogens; 3. GF—gingival fibers; 4. substances: LPS—lipopolysaccharide, BEPs—bacterial extracellular proteinases, VFs—other virulence factors, e.g., gingipain proteases or leukotoxin, Ig—immunoglobulins, TNF-α—tumor necrosis factor alpha, IFN-γ—interferon alfa, GM-CSF—granulocyte-macrophage colony-stimulating factor, MMPs—matrix metalloproteinases, CK—cytokines, ILs—interleukins, M-CSF—macrophage colony-stimulating factor, PGE2—prostaglandin E₂, LTB4—leukotriene B4, CTSG—cathepsin G, CTSK—cathepsin K, DF—defensins, NE—neutrophil elastase, ROS—reactive oxygen species, CA II—carbonic anhydrase II, RANKL—receptor activator of nuclear factor kappa-Β ligand, SPT—serine proteases, H—histamine, PG—proteoglycans, CS—complement system factors, uPA—urokinase-type plasminogen activator, tPA—tissue plasminogen activator, ADAMs—a disintegrin and metalloproteinase, (NO)—nitric oxide, (TIMPs)—tissue inhibitors of metalloproteinases, and (OPG)—osteoprotegerin (substances listed in brackets are involved in preventing tissue destruction, in contrast to some other listed substances). Created with BioRender.com.