Biochemical Role of Matrix Metalloproteinase -9 in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune pathology associated with a chronic inflammatory process, which can damage both joints and extra-articular organs, including the heart, kidney, lung, digestive system, eye, skin and nervous system.(Cojocaru et al. 2010, Conforti et al. 2021).

Rheumatoid arthritis affects most commonly the hand, wrist, and foot, but it can also affect large joints .IT is characterized by painful, swollen joints that can severely impair physical function and quality of life and associated with increased mortality (Sparks et al. 2016). About 70% of patients with RA are women, and peak incidence is between ages 50 and 60 years (Sparks et al. 2019).

Matrix Metalloproteinases are a family of calcium-dependent endopeptidases with a zinc-binding active side. More than 20 different MMPs are classified according to the particular substrates they degrade: collagenases, stromelysins, gelatinases, matrilysins, membrane-type MMPs, and others. Moreover, MMPs release growth factors from carrier proteins, inactivate proteinase inhibitors, and influence inflammatory cytokines and chemokines that can also be responsible for joint destruction(Nagase et al. 2006) .

In the human body, MMPs are synthesized in leukocytes, macrophages, endothelial cells, and connective tissue cells such as chondrocytes and synoviocytes, both found in the knee joint. Matrix metalloproteinases are secreted as pre-proenzymes into the extracellular fluid, where they can be activated by a variety of substances: epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and other MMPs. Conversely, steroid hormones, transforming growth factor-β (TGF-β), plasma proteins such as a2-macroglobulin and a1-antitrypsin, and tissue inhibitors of metalloproteinases (TIMPs) can inhibit MMP activity(Visse and Nagase 2003).

The pathogenesis of RA is based on the fact that the patient's body reacts to autoantigens, e.g. citrullinated peptides, or a foreign peptide, e.g. a viral or bacterial peptide that is cross-reactive with an autoantigen (Kwon and Ju 2021).

Activated T cells, B cells, and monocytes infiltrate the synovial membrane in joints, as that is where the autoantigens accumulate. Cytokines and chemokines secreted by leukocytes, such as tumor necrosis factor, IL-6, and granulocyte colony-stimulating factors activate endothelial cells, stimulate neovascularization and leukocyte migration, and cause expansion of synovial fibroblast-like and macrophage-like cells (Alivernini et al. 2022). Expansion of these cells leads to a hyperplastic synovial lining layer referred to as a "pannus". The pannus invades the periarticular bone at the cartilage-bone junction and leads to the progressive destruction of cartilage and subchondral bone tissue(Aletaha and Smolen 2018).

Matrix metalloproteinases are crucial for the pathogenesis of RA. Synovial fibroblast-like cells, having a tumor-like appearance, secrete various proteases, including MMPs that degrade ECM components, mainly proteoglycans, and collagens, of articular cartilage in the affected joints. Expression of the following MMPs is upregulated in synovial tissue: MMP-1, -3, -9, and -13 (Vincenti and Brinckerhoff 2002, Heard et al. 2012, Araki and Mimura 2017).