Introduction

Matrix metalloproteinases (MMPs)-a group of over 20 zinc-dependent proteases—have the fascinating capability to degrade different types of extracellular matrix (ECM) proteins. Among these MMPs, MMP12 stands out for its significant role in maintaining mucosal integrity and regulating various pathological processes, including inflammation, cancer, and fibrosis.

Fig. 1 The role of MMP12 in the oral environment (Lin B., et al. 2023).

What is MMP12?

MMP12 is an extracellular enzyme that was first discovered in the alveolar macrophages of smokers and then categorized under the matrix metallopeptidase family due to its similar genomic structure and activity. This full-length enzyme comprises three domains: an amino-terminal propeptide domain, a zinc- and calcium-binding catalytic domain, and a carboxy-terminal haemopexin-like domain. These domains collectively determine the enzyme's latency, catalytic activity, and substrate specificity.

Released initially as a 54-kDa pro-form enzyme, MMP12 undergoes autolysis to create 45-kDa and 22-kDa products. Besides auto-proteolytic processing, MMP12 can activate additional MMPs like pro-MMP1 and pro-MMP9. This enzyme also has a broad range of ECM substrates, such as type IV collagen, fibronectin, laminin, vitronectin, chondroitin sulfate, and heparan sulfate proteoglycan. Moreover, an interesting facet of MMP12 is its intracellular role in macrophages, where it can kill bacteria directly, being characterized as a novel antimicrobial peptide.

The Enigmatic Presence of MMP12 in Oral Tissues

While MMP12's roles in systemic diseases have been extensively studied, its function in the oral environment remains less explored. Recent studies, however, have started lifting the veil on this enigmatic enzyme, revealing its involvement in both normal oral tissue homeostasis and various oral disorders.

Under normal conditions, MMP12 is barely detectable in adult tissues, except in areas undergoing rapid remodeling, such as the placenta during fetal development. However, it does make its presence known in certain oral tissues like the gingiva, periodontal ligament, and even dental pulp. Single-cell RNA sequencing data has shown that MMP12 is particularly expressed in myeloid cells and epithelial cells within these tissues. This suggests that while its basal levels are low, MMP12 may play a role in maintaining tissue integrity and immune response.

MMP12's Role in Oral Diseases

Periodontal Disease

Periodontal diseases, such as chronic periodontitis, are often driven by dysregulated inflammatory responses and excessive production of tissue-remodeling enzymes like MMPs. MMP12, known for its elastin-degrading capability, has been linked to periodontal tissue degradation. Elevated levels of MMP12 in saliva correlate with severe periodontal inflammation. Post-treatment reductions in MMP12 in the GCF of aggressive periodontitis patients suggest its potential as a diagnostic marker.

However, the expression of MMP12 varies across different periodontal conditions. For instance, it is significantly lower in idiopathic gingival fibromatosis (IGF) tissues compared to normal gingiva. This indicates that low MMP12 expression might contribute to gingival enlargement due to impaired protein hydrolysis. Conversely, MMP12 is upregulated in the gingival overgrowth tissues of periodontitis patients, suggesting diverse roles depending on the inflammatory context.

The underlying mechanisms that govern MMP12 expression involve various inflammatory pathways. Cytokines like TNF-α and IL-1β induce MMP12 expression in the dental pulp and gingival fibroblasts, while CSF-2 stimulates MMP12 production in monocyte-derived cells. These interactions highlight the complex regulatory network involving MMP12 in periodontal diseases.

Bone Remodeling and Orthodontic Tooth Movement

MMP12's role in bone remodeling is less clear but intriguing. While MMP12 is expressed in bone-resorbing cells like osteoclasts, it doesn't significantly degrade type I collagen, the major component of bone and dentin matrices. However, MMP12 may influence osteoclast-matrix interactions and contribute to cartilage degradation in rheumatoid arthritis.

In orthodontic tooth movement, MMP12 expression increases following mechanical loading and may aid in ECM remodeling that facilitates tooth movement. Elevated MMP12 levels have been observed 24 hours after activating periodontally involved teeth undergoing orthodontic treatment, hinting at its regulatory role in orthodontic stress responses.

Oral Squamous Cell Carcinoma (OSCC)

MMP12 is implicated in the development and progression of various cancers, including OSCC. Aberrantly high MMP12 levels have been observed in OSCC patients compared to healthy individuals and those with oral submucous fibrosis (OSF). Interestingly, lower MMP12 levels in metastatic OSCC compared to nonmetastatic cases suggest that MMP12 might serve as a prognostic marker.

Temporomandibular Joint Dysfunction (TMD)

TMD often involves chronic inflammation and degradation of TMJ disc elements. Increased MMP12 expression in TMD patients indicates its role in elastin degradation and chronic inflammation. Studies on TMJ osteoarthritis models confirm that MMP12 is associated with tissue inflammation and degradation.

Potential Therapeutic Approaches

Given its significant role in various oral diseases, targeting MMP12 presents a promising avenue for diagnosis and therapy. High MMP12 levels in saliva can serve as non-invasive diagnostic markers for periodontal diseases, OSCC, and TMD. Advanced diagnostic tools and chair-side tests could monitor MMP12 levels to predict disease status.

Pharmacologically, specific MMP12 inhibitors are being developed for lung diseases, and repurposing these inhibitors could benefit oral disease management. For instance, doxycycline, known for its broad-spectrum antibiotic activity, has shown potential in reducing MMP12 activity and improving periodontal health outcomes.

Probiotics also offer an interesting therapeutic strategy. Specific strains like Lactobacillus and Bifidobacterium reduce MMP12 expression in inflammatory conditions, suggesting their potential to modulate oral microbiota and inflammatory responses, thus benefiting periodontal health.

Conclusion

MMP12 is an enzyme with far-reaching implications across various physiological and pathological processes, particularly within the oral environment. Its role spans from maintaining tissue integrity and immune responses to influencing disease progression and therapeutic outcomes. Unveiling the precise mechanisms by which MMP12 operates can lead to improved diagnostic and therapeutic strategies, enhancing oral health and overall well-being. As research progresses, targeted interventions harnessing the power of MMP12 could revolutionize the management of oral diseases, ushering in a new era of precision medicine in dentistry.