Ankylosing spondylitis (AS) is an autoimmune disorder that mostly affects the sacroiliac joints and the spine. People suffering from this disease typically complain about spinal stiffness and back pain as a result of enthesitis and vertebrae fusion. AS usually starts at an early age and it is believed that one in every two hundred people is influenced by this disease, making it an important health issue [1, 2]. The exact etiology by which the disease is started is still unknown; however, The most important contributors to disease creation are supposed to be hereditary and environmental causes . Diverse environmental factors, infectious diseases, and gut dysbiosis in genetically predisposed people, which is defined by possessing certain human leukocyte antigen (HLA) and non-HLA genes including HLAB27, IL23R, ERAP1, and certain TLRs alleles; can cause disease occurrence [4, 1, 5].
Different signaling pathways are involved in autoimmune diseases. One of which is the adenosinergic pathway . To date, available data show that the adenosinergic pathway has a tremendous impact on immunosuppression and aids the body to recover from excessive inflammatory responses. Adenosine is a byproduct of the breakdown of an enzyme cascade, consisting of CD39 (ecto-nucleoside triphosphate diphosphohydrolase 1,
E-NTPDase1) breaks down adenosine triphosphate/diphosphate (ATP/ADP) to adenosine monophosphate (AMP) and CD73 (ecto-50-nucleotidase, NT5E) produces adenosine from AMP. Adenosine acts through G-protein-coupled cell-surface receptors which are expressed on a variety of cells, and to date four of them A1AR, A2AAR, A2BAR, and A3AR; are recognized. These receptors are known as type 1 purinergic (P1) receptors [7, 8, 6].
Bone morphogenetic proteins (BMPs) are important members of the transforming growth factor superfamily with multiple vital roles such as embryonic development and osteoblastic differentiation . Of these, BMP-2 is an active and important member which can independently or synergistically with other signaling pathways like the Wnt/β-catenin pathway, enhance osteoblast differentiation and bone formation [10, 9]. Data regarding the level of these proteins in AS patients are incompatible; however, most of them show higher levels of these proteins in patients compared to healthy controls [11, 12].
Matrix metalloproteinases (MMPs) are a family of 23 zinc-dependent enzymes produced by a variety of cells especially immune cells in the event of an inflammatory situation. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-6 are produced in this environment [13, 14]. These proteins are mostly involved in the degradation and remodeling of extracellular matrices in humans . High levels of MMPs have been seen in inflammatory autoimmune diseases like rheumatoid arthritis (RA). Different studies showed the relation of high levels of MMP-3 and its certain single nucleotide polymorphisms (SNPs) with AS occurrence [15, 16]. Along with the studies showing the relation of MMP-3 and AS, the correlation of bath AS disease activity index (BASDAI) with a group of clustered biomarkers comprising MMP-8, MMP-9, chemokine (C-X-C motif) ligand (CXCL)-8, and hepatocyte growth factor was found . MMP-8 expression is related to inflammatory cytokines and it can have cartilage destructive activities during spondyloarthropathies. One of the SNPs of this enzyme has also been found to be associated with the risk of AS. MMP-9, also called gelatinase B, along with MMP-2 (gelatinase A), are mediators of joint destruction [18, 15].
It is known from previous studies that Inflammatory lesions and the overlaying synovium of spondyloarthritis (SpA) are dominated by macrophages, which are mostly responsible for the breakdown of fibrocartilage [4, 19, 20]. The inflammatory activities of macrophages can be regulated by P1 receptors through binding to adenosine . The expression of proteins responsible for the pathogenesis of AS in macrophages is an important issue to consider for the treatment and control of the disease progression, so we aimed to evaluate the expression level of MMP3, 8, 9, 13, and BMP2, and 4 in macrophages of AS patients in an untreated situation and after treatment with A2AAR agonist (CGS-21680) as no study has done this up until now.