Introduction

Matrix metalloproteinases (MMPs) are a large family of Ca²⁺ and Zn²⁺-dependent proteolytic enzymes that play a crucial role in various physiological processes by cleaving the components of the extracellular matrix (ECM) and other regulatory molecules. The balance between MMPs and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), is essential for maintaining oral health. In recent years, significant attention has been directed toward understanding the functions of MMP-8 (collagenase-2 or neutrophil collagenase), particularly in the context of periodontitis, peri-implantitis, and carious lesions.

Introduction to MMPs

Matrix metalloproteinases (MMPs), often referred to as "matrixins," are a group of proteolytic enzymes that depend on calcium and zinc ions to function. Their primary role is to degrade various components of the extracellular matrix (ECM), such as collagen, elastin, gelatin, and proteoglycans. In addition, MMPs can process a range of other molecules, including growth factors, cytokines, chemokines, and adhesion proteins, thereby influencing numerous cellular processes such as angiogenesis, apoptosis, cellular differentiation, embryogenesis, wound healing, and immune responses.

The MMP family in humans consists of more than 23 members, which are categorized into six main groups based on their substrate specificity and structure: collagenases, gelatinases, matrilysins, stromelysins, membrane-type MMPs, and other MMPs. These enzymes are expressed and secreted by various cell types, including neutrophils, macrophages, endothelial cells, epithelial cells, vascular smooth muscle cells, glial cells, and tumor cells. Upon activation, these cells release MMPs alongside regulatory molecules like interleukins (IL-8 and IL-1β), tumor necrosis factor (TNF)-α, osteoprotegerin (OPG), prostaglandins (PGE2), and receptor activator of nuclear factor kappa-B ligand (RANKL).

MMPs are synthesized as inactive proenzymes (proMMPs), and their activity is tightly regulated through gene expression, proenzyme activation, and inhibition by TIMPs. In humans, there are four types of TIMPs (TIMP-1 to TIMP-4) that regulate the activity of MMPs and play a key role in the remodeling and replenishment of the ECM. The balance between MMPs and TIMPs is crucial for maintaining tissue homeostasis, and any disruption in this balance can lead to pathological conditions.

MMPs in Oral Health

In the oral cavity, MMPs are expressed by various cell types, including gingival fibroblasts, keratinocytes, neutrophils, macrophages, and epithelial cells. These enzymes are involved in multiple aspects of oral health, from the development of dental structures to the maintenance of periodontal tissues and the response to microbial challenges.

Fig. 1 Secretion in oral fluid of MMP-8 and several regulatory molecules by activated polymorphonuclear leukocytes (PMNs) and non-immune cells (gingival epithelium) and fibroblasts in gingival connective tissue (Atanasova T., et al. 2023).

One of the most studied MMPs in the context of oral health is MMP-8, also known as collagenase-2 or neutrophil collagenase. MMP-8 is primarily expressed by neutrophils, which are key players in the immune response to bacterial infections. However, other cell types, including macrophages, fibroblasts, and epithelial cells, can also produce MMP-8 under certain conditions.

MMP-8 plays a crucial role in the degradation of type I collagen, the most abundant collagen in the periodontium. This activity is essential for normal tissue remodeling but can lead to pathological tissue destruction when dysregulated. Elevated levels of MMP-8 have been associated with various oral diseases, including periodontitis, peri-implantitis, and dental caries.

MMP-8 in Periodontal Diseases

Periodontal diseases, including gingivitis and periodontitis, are among the most common inflammatory conditions affecting the oral cavity. These diseases are characterized by the destruction of the supporting structures of the teeth, including the gingiva, periodontal ligament, and alveolar bone. The primary cause of periodontal diseases is the accumulation of bacterial biofilm (plaque) on the teeth, which triggers an immune response that can lead to tissue destruction.

MMP-8 plays a central role in the pathogenesis of periodontitis by degrading type I collagen in the periodontal ligament and alveolar bone. Elevated levels of MMP-8 have been detected in the gingival crevicular fluid (GCF) of patients with periodontitis, correlating with the severity of the disease. This makes MMP-8 a potential biomarker for the diagnosis and monitoring of periodontitis.

MMP-8 and Peri-Implantitis

Peri-implantitis is a pathological condition that affects the tissues surrounding dental implants, leading to inflammation, bone loss, and ultimately implant failure. The etiology of peri-implantitis is similar to that of periodontitis, involving the accumulation of bacterial biofilm and the host's immune response.

Like periodontitis, peri-implantitis is associated with elevated levels of MMP-8 in the peri-implant sulcular fluid (PISF). MMP-8 contributes to the degradation of the collagen matrix in the peri-implant tissues, leading to bone resorption and implant instability. The detection of elevated MMP-8 levels in PISF can serve as a diagnostic marker for peri-implantitis, helping clinicians identify and treat the condition before significant bone loss occurs.

MMP-8 in Dental Caries

Dental caries, commonly known as tooth decay, is another prevalent oral disease characterized by the demineralization of tooth enamel and dentin due to acid production by cariogenic bacteria. While the primary focus in caries research has been on the role of bacterial biofilm and acid production, recent studies have highlighted the involvement of host-derived enzymes, including MMPs, in the progression of carious lesions.

MMP-8, along with other MMPs such as MMP-2, MMP-9, and MMP-20, has been implicated in the degradation of the organic matrix of demineralized dentin. During the carious process, bacterial acids lower the pH in the oral environment, leading to the activation of dentin-bound MMPs. Once activated, these enzymes degrade the collagen matrix in the demineralized dentin, further weakening the tooth structure and facilitating the progression of caries.

The role of MMP-8 in dental caries has opened new avenues for therapeutic intervention. Inhibitors of MMP activity, such as chlorhexidine and bisphosphonates, have been explored as potential treatments to prevent the degradation of the dentin matrix and slow the progression of carious lesions. Additionally, the development of diagnostic tools that measure MMP-8 levels in saliva or dental tissues could aid in the early detection and management of dental caries.

Conclusion

Matrix metalloproteinase-8 (MMP-8) plays a significant role in both physiological and pathological processes within the oral cavity. Due to its involvement in periodontal tissue remodeling, inflammation, and various disease states, MMP-8 serves as a critical biomarker and potential therapeutic target. The assessment of MMP-8 in clinical settings, particularly for diagnosing and monitoring periodontitis, peri-implantitis, and caries, holds promise for improving patient outcomes.