MMP3 as a Molecular Link: Unraveling the Connection Between Ankylosing Spondylitis and Acute Coronary Syndrome

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the joints, limiting patients' mobility and quality of life. Recent studies have shown that patients with AS have a significantly higher risk of developing severe cardiovascular complications, such as acute coronary syndrome (ACS). A comprehensive review (2014-2024) included a study evaluating the significance of matrix metalloproteinase 3 (MMP-3) in cardiovascular risk among AS patients. The findings indicate that chronic inflammation in AS not only damages the joints but also contributes to the progression of cardiovascular diseases. At the molecular level, MMP-3 is instrumental in degrading the extracellular matrix, leading to instability in the atherosclerotic plaques and increasing the risk of ACS. Additionally, MMP-3 activation is related to the inflammatory pathways, such as tumor necrosis factor-alpha (TNF-α) and NF-κB, which amplify its effect on both joint destruction and vascular damage. This molecular approach offers new perspectives for understanding and treating AS and its cardiovascular complications, suggesting that MMP-3 inhibition could be a promising therapeutic strategy to mitigate cardiovascular risk in these patients.

Keywords: acute coronary syndrome; ankylosing spondylitis; cardiovascular risk; chronic inflammation; extracellular matrix degradation; matrix metalloproteinase 3 (MMP-3).

Figure 1

The image shows a detailed diagram of the signaling pathways that regulate the expression and activation of MMP-3 (matrix metalloproteinase 3), highlighting its role in extracellular matrix degradation and the activation of other MMPs. At the top, the activation of the NF-κB and MAPK pathways is observed through TNF-α and IL-1β signals, which bind to their respective receptors (TNFR1 for TNF-α and TAK1 for IL-1β) on the cell membrane. This activates signaling proteins such as TRADD, TRAF2/5, RIP1, and various kinases like MKK, MEK, and JNK/p38, which ultimately phosphorylate and activate NF-κB. This transcription factor translocates to the nucleus, where it promotes MMP-3 expression. At the bottom, MMP-3’s interaction with other metalloproteinases (MMP-1, MMP-10) and their tissue inhibitors (TIMP1, TIMP2) is shown, evidencing a complex regulatory system where MMP-3 not only acts directly but also modulates the activity of other MMPs. Additionally, interaction with SPP1 (extracellular matrix protein) involved in tissue degradation is observed, underscoring the central role of MMP-3 in inflammatory processes and tissue remodeling.

Figure 2

MMP-3 in the pathological link between AS and ACS. The upper section represents cytokines (e.g., TNF-α, IL-6, IL-1, and IL-17) involved in AS that stimulate the production of MMP-3 by macrophages, fibroblasts, and endothelial cells in the synovial lining. MMP-3 facilitates extracellular matrix (ECM) degradation and promotes inflammatory cell recruitment and vascular invasion. In the lower section, these processes contribute to key events in ACS, including plaque rupture, neovascularization, and cell proliferation, highlighting the shared inflammatory and tissue remodeling pathways between AS and cardiovascular complications.