Rheumatoid Arthritis and Matrix Metalloproteinases - Essay Example

Rheumatoid arthritis and Matrix Metalloproteinases (MMPs MMPs role in the disease process, as a diagnostic tool, and therapeutic target. Instructor University Date of submission “Rheumatoid arthritis and Matrix Metalloproteinases (MMPs): MMPs role in the disease process, as a diagnostic tool, and therapeutic target.” Rheumatoid arthritis is defined as a systemic autoimmune disorder, which is marked by chronic and symmetrical erosion of the inflamed synovial joints (Frontera et al 2008, pg. 203). It differs from osteoarthritis as it is characterized by the chronic inflammation of synovial joints, rather than being a disease of deteriorating articular cartilage (characteristic of osteoarthritis) which is brought about by the articular chondrocytes releasing deleterious proteinases (Takaishi et al 2008, pg. 47). This disease can last from a few months up to several years and involves the inflammatory swelling of joints with extensive involvement of soft tissues. It is further accentuated by chronic involvement of similar joint regions of both upper and lower extremities, specifically the metacarpophalangeal and metatarsophalangeal joints. An interesting aspect of this disease is that it often goes unnoticed until the symptoms worsen due to the absence of associated infections, and thus a positive marker test aids in its diagnosis (Weisman, 2011 pg. 5). Although the disease is not prevalent in the world to great extent, its symptoms show radical progression after ten years of diagnosis and lead to severe pain and stiffness in joints (Frontera et al 2008, pg. 204), which greatly hampers mobility of the distal limbs and functionality, and therefore leads to a poor quality of life. In order to diagnose rheumatoid arthritis during its early stages, as well as for the purposes of overall epidemiologic classification, scientists developed a criteria for the classification of the disease. The first ever criterion was publishes in 1958, which was then revised thirty years later, in 1988. However, due to the severity and prevalence of this disease, changes in its classification are ongoing as researches are duly being published. According to Harris’ study, there are five stages of rheumatoid arthritis. It delineates that proper care and treatment should be given in stages one and two in order to prevent the spread of rheumatoid arthritis to laterstages, that is, before the damage becomes irreversible and recovery is impossible(Harris, 1990, pg. 1277). As inflammatory changes progress, the first stage of rheumatoid arthritis is characterizes by antigen presentation to the T-cell, with scarcely any symptoms or solid radiographic evidences. However, as the diseases progresses towards stage two, T-cells proliferate, along with the proliferation of B-cells, resulting in fever and malaise, as well as the characteristic morning stiffness of joints – though only to a mild extent.Synovial membrane, during the second stage shows angiogenesis, another characteristic sign of the progression of inflammation. Slight swelling of joints may also be noticed in this stage. The radiological changes are still near insignificant during this stage. Nonetheless, the patient may display symptoms of swollen joints of hands and feet as well as knee joints. Treatment options therefore warrant early diagnosis of rheumatoid arthritis during these two phases so as to prevent further spread towards disease chronicity (Harris, 1990, pg. 1278). During the third stage, the cells lining the synovium start to proliferate, along with the proliferation of neutrophils. The proliferation of the synovial membrane cells however, does not involve cartilage at this point; therefore cartilage destruction is minimal and thus can be prevented if prompt action is taken. The symptoms are characteristically same as those of the second stage including generalized weakness in the body, as occurs during long term inflammation. The physical signs to look for in patients suffering from this particular stage of rheumatoid arthritis would be warmth in the swollen joints, along with excessive synovial fluid, as produced by the proliferating cells of synovial membrane. Furthermore, tissue proliferation within joints occurs, which leads to increasing amount of pain in the joints. The rheumatoid nodules also begin to appear in this stage, resulting in soft-tissue swellings noted on the radiographs (Harris, 1990, pg. 1278). The fourth and fifth stages of rheumatoid arthritis as explained by Harris are those from which recovery may not be possible. It should be kept in mind, however, that recovery denotes only symptomatic treatment of this disease. Such a damaging condition is deemed irreversible due to the polarisation of synovial joint inflammation to produce invasive pannus that is, excessive vascular fibrosis, and thus more restriction in movement. Moreover, destruction of cartilage begins at stage four as chondrocytes are activated and proteinases such as MMPs begin the destruction of the ECM. The swellings therefore become more pronounced and radiographic evidence is conclusive of periarticular osteopenia as the pannus reveals itself on the MRI (Harris, 1990, pg. 1278). The final stage as described by Harris includes the proliferation of inflammatory substrates to reach and begin destruction of the bone. The subchondral bone becomes eroded, along with the invasion of cartilage by the pannus. Due to these effectsof erosion, the ligaments stretch around joints, enhancing the pain for patients. The symptoms now begin to include bone deformities such as ulnar deviation at the metacarpophalangeal joints. Physical signs start to include all the things which lead the patient against motility. These comprise of contractures upon flexing the joints, and decreased stability of joints. Radiography during this stage shows narrowing of joints, as is evident due to the increased proliferation of chondrocytes(Harris, 1990, pg. 1278).The quality of life for patients thus becomes worse as movement becomes restricted and they have to depend on others for help. The pathophysiology of rheumatoid arthritis comprises of an elevated rheumatoid factor, a protein identified in the IgG and IgA classes of immunoglobulins found in humans (Herman, 1973, pg. 116). Its later stagesconcernmarked degradation of extracellular matrix (ECM)of the cartilage mediate by various proteinases, coupled with inflammation of the joint synovium which proliferates with time. This proliferation, due to abnormal immunologic mediation causes hyperplasia of the cells lining the synovial joints and thus causes invasion of the synovium with inflammatory cells and subsequent angiogenesis. This leads to further degradation of the articular cartilage (Takaishi et al 2008, pg. 47). Articular joint cartilage comprises of an ECM which consists of chondrocytes. This ECM is composed of major and minor proteoglycans, depletion of which is a common change in the initial stages of joint diseases followed by the degradation of collagen fibrils. One of the major proteoglycans is Aggrecan, components of which are degraded by “matrix metalloproteinases (MMPs), ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs species, neutrophil elastase, cathepsin G, and cathepsin B”. Once Aggrecan is degraded, the type II collagen is degraded with the aid of typical collagenases including MMP-1, MMP-8 and MMP-13, and type IX and X collagen is degraded by MMP-3. Once the collagen molecules are cleaved they get denatured to form gelatin, and gelatinases (MMP-2 and MMP-9) break them down further (Takaishi et al 2008, pg. 47, 48). The articular cartilage, in rheumatoid arthritis, is degraded by both synovitis as well as the affected chondrocytes. MMP-1 is produced in excess by the cells lining the synovium along with MMP-3, MMP-9 as well as tissue inhibitor of metalloproteinases (TIMP) -1 and TIMP 3. In response to the inflammation, leukocytes that invade and enter the synovium secrete MMP-8 and 9 as macrophages secrete MMP-1, 9, TIMP – 1 and 2. All these intermediates are secreted as the sequence of events mediating chronic inflammation follow, however, amidst them MMP-3 is secreted in exceptionally high levels as compared to other MMPs (Takaishi et al 2008, pg. 48). Where MMPs are concerned, they are called matrix metalloproteinases, because they are a family of over twenty proteinases that were originally identified as enzymes which merely degraded the ECM substrates, and thus provide a major role in ECM homeostasis and consequently, chronic inflammation. However it has recently been discovered that they oppose angiogenesis not only due to their original functionality, but also by releasing inhibitors of angiogenesis. The inhibitors are released as plasminogen is digested by MMPs to produce angiostatin, and endostatin via digesting the type XVIII collagen. Another one of their functions is to cleave growth receptors and facts that are bound to the surface of the cellsand release these factors from ECM (known as integrin signalling). They also control apoptosis via release of certain survival factors. However, their most important effect is considered to be of immunological host defense and to control the bioactivity of chemokines (Clark et al 2008, pg. 1363). In the aforementioned article Clarke mentions the various factors by which MMPs can be expressed by acetylation, methylation and mRNA stability. The regulation of MMPs, on the other hand can be controlled by gene expression at promoter level or at the level of post transcriptional levels. This denotes the excessive research in the field of biochemistry and genetics that was undertaken in order to classify and detect how the MMPs relate to and can be used as a diagnostic and therapeutic tool where rheumatoid arthritis is concerned. Although MMPs have further been classified into collagenases, gelatinases, stromelysins and membrane type MMPs according to the site on which they act, their structure and location in the cells; several new enzymes that fall into this category do not strictly adhere to these divisions due to their own domain, structure and site within the cells (Clark et al 2008). In most of the researches, various MMPs have been classified as having integral role in the progression of the disease. This can be vouched for by the various tests conducted by the researchers during their trial. The first criterion that marks the progressiveness of MMP evaluation proves to be positive for demonstrating progressiveness of the disease, as per “Green’s study”(Mamehara et al 2010, pg. 104). Nonetheless, since it has been mentioned earlier that rheumatoid arthritis is a disease that can commence from and last for a few months to several years, another research conducted within one year’s duration had been examined thoroughly after their history being taken and their swollen and tender joint counts taken. This research can be deemed thorough as it took into account all the possible factors contributing to the progression of rheumatoid arthritis and concluded that MMP-1 and MMP-3 tend to be higher in patients with rheumatoid arthritis (Green et al 2003, pg. 84, 85). Thus the idea of progression of this systemic disease is showcased. MMP-3, is deemed to be a proteolytic enzyme which is thought to be characteristic of the destruction of synovial joint in rheumatoid arthritis. MMP-3 is produced locally in the joint inclusive of synovitis and released into the bloodstream MMP-3 is locally produced in the inflamed joint, and released into the blood stream. With the progression of rheumatoid arthritis, more and more MMP-3 is released into the blood stream. Thus MMP-3becomes characteristic of the autoimmune disease that is rheumatoid arthritis, essentially a systemic marker that shows the level of activity to which the joints have been inflamed. Moreover, MMP-3 may be called an inflammatory marker of the synovium of the joint, unlike C-reactive protein (CRP), which is also a marker, but is not produced during inflammation, hence a non-inflammatory marker (Mamahera et al 2010, pg.98). Another important matrix metalloproteinase, MMP-13 has sparked the interest of quite a few scientists who believe it to play an important role in osteoarthritis and rheumatoid arthritis due to its bone resorption activity (Takaishi et al 2008, pg. 50), however, it can be concluded that most scientists would agree with the result of MMP-3 serving as one of the main cytokines to aid doctors and scientists to evaluate the progression of the disease. This is due to the fact that it expresses itself within one year, and over a span of years can be used to monitor the extent to which the disease has spread so that it can be re-evaluated and treated promptly. These realisations have been brought about by the comparative study of the aforesaid researches. Where diagnosis of rheumatoid arthritis is concerned, a standard protocol has been followed by physicians. Even though the method is quite extensive albeit thorough, it is essential to be followed in order to explicate the validity of MMP presence substantial to its cause. The initial requirements as per any other diseases are taking a complete history and physical assessment, in order to localize the area of concern. This is followed by noting the swollen and tender joint counts. The count was followed by a Health Assessment questionnaire in the research conducted by Green (Green et al 2003 pg. 84), which included 10cm visual analogue scores to assess the patient’s extent of disease, activity and the amount of pain he is in. The questionnaire was to be calculated on a scale of 0-24, and also included a record of the assessment of disease activity by the observer, scored between 0 and 4. Besides this the mandatory aspects to note down in diagnosis of rheumatoid arthritis include the complete blood count (CBC), plasma viscosity, erythrocyte sedimentation rate, a test of all the electrolytes and blood glucose levels. Apart from this, liver enzymes, calcium, urate and thyroid function also aid the diagnosis of rheumatoid arthritis. The most important diagnostic tests, perhaps is the tests for rheumatoid factor (RF) and C-reactive protein (CRP) as these are cytokines and proteins that are causative to chronic inflammation of the synovial joints. The values of RF and CRP are determined by blood tests, which often also includes antinuclear factor and immunoglobulins and IgM wherever required (Green et al 2003 pg. 84). Radiological examination – including that by Magnetic Resonance imaging as well as X rays is recorded. Usually, since the metacarpophalangeal and metatarsophalangeal joints are affected, as mentioned above, it is the distal limbs that show positive signs and should therefore undergo proper radiographic examination. Enzyme-linked immunosorbent assay (ELISA) is the latest and perhaps most authentic technique in identifying the key enzymes present in rheumatoid arthritis. Perhaps this is why Green’s aforementioned researched used double-antibody ELISA for MMP-1 and MMP-3. In the particular investigation, samples were stored at a particular temperature and ELISA was used to measure serum constituents. It is important to note that for different investigations, different antibodies have been used. However in this research, the antibody was raised to the inactive pro-MMP and used in order to ultimately compare MMP-3 to other commercially available assay. However, Green evaluates and reaches the conclusion that despite using different antibodies, both MMP-3 assays measure the same protein in circulation (Green et al 2003 pg. 84). The ELISA method is perhaps the most important diagnostic feature with the concern of this article regarding the diagnostic features of rheumatoid arthritis along with measurements of Rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA) and C-reactive protein (CRP) (Mamahera et al 2010, pg.98). These inflammation mediators are important as they assist not only the evaluation of the disease progression and are a diagnostic tool, but they are also essential components of therapeutic markers as will be explored further. Rheumatoid arthritis is a disease that is prevalent highly amidst women of a middle age (Columbus, 2005, pg.2) and being an autoimmune disease of the system that is chronic in onset and inflammatory in nature;it has no particular cure developed for, except the treatment of its symptoms that is cure from the intense pain that patients would otherwise suffer. As explained above, cytokines are the mediators of chronic inflammation and are essential in the progression of systemic autoimmune disorders such as rheumatoid arthritis. Therefore they bring about pro-inflammatory effects, the negation of which is absolutely essential, in order to cause the cessation of the inflammatory outcomes. Therefore, the treatment plan of action now involves several anti-cytokines. These drugs are available in the market and are known as disease modifying anti- rheumatic drugs (DMARDs). If biological DMARDs are given, they need to be given via the parenteral route that is through intravenous infusion or subcutaneous injection, since they are proteins. They can either be used singularly, or in combination with other DMARDs, particularly methotrexate(Nijkamp&Parnham, 2005, pg. 590). In the study by Mamehara, it has been pointed out that throughout the course of time, several studies shine light upon using tumor necrosis factor (TNF) blocking agents as DMARDs, since their efficacy in reducing the degradation of synovial joint tissue that is brought up on the radiographic images is good. However, the same study argues that even though the efficacy of TNG blocking agents knows no parallel, they still possess a major drawback. This drawback pertains to the TNF blocking agents being too expensive as well as being fraught with major side effects. It is therefore suggested to use non-biological DMARDs and evaluate their response in patients with such radiographic evidence. These non-biological DMARDs would be designed to work against the various chemical mediators, as is the process of each mediator during each stage in the development of rheumatoid arthritis, and thus stop the inflammatory process right there. The markers may be non-specific to the cause such as CRP or ESR, or specific such as ACPA, RF or MMP-3 (Mamahera et al 2010, pg.99). The revelation of extensive use of DMARDs as a therapeutic strategy until stage III of rheumatic arthritis relates it to the use of not only MMP-3 but also other MMPs, such as MMP-13 as explained above. Takaishi’s research focuses on the fact that MMP activity is in itself controlled at many levels, included gene expression of MMPs, transcription and secretion of MMPs, and the fact that activation of pro-MMps as well as inhibition of MMPs by natural inhibitors such as TIMP occurs at the time of their synthesis, in order to regulate the synthesis of inflammatory products within the cytoplasm. TIMP being a natural inhibitor of MMP in joint tissue has been evaluated as potential signal transduction inhibitor and thus, marked as a source of treatment for rheumatoid arthritis (Takaishi et al 2008, pg. 51). In essence, many scientists do focus on the importance of natural factors to treat rheumatoid arthritis, be it related to metalloproteinases, specific or non-specific cytokines. Yet, they also exhibit a reluctance to start administering them because of the fact that either they are difficult to obtain, or they are expensive, or perhaps these markers are too heavy for humans to consume. Since rheumatoid arthritis is a disease which will degenerate in approximately sixty percent of the cases, as noted above, the heavy molecules of medicines may end up causing further complications. The 2012 revision of ACR recommendations for therapeutics of rheumatoid arthritis included treatment and indications with DMARDs and biological agents, when and how to switch between DMARDs and biologic therapies as well as the different therapeutic strategies used for patients who were co morbid with diseases such as ulcerative colitis. The aforementioned revision also included the vaccination indication for certain diseases, the chances of which may be prevalent during rheumatoid arthritis. According to the recommendations, the DMARDs commonly used (either singularly or in combination) included hydroxychloroquine, leflunomide, methotrexate, minocycline and sulfasalazine. The biologic agents included both non TNF as well as anti-TNF drugs. The non TNF drugs comprised of abatacept, rituximab and tocilizumab; whereas the anti-TNF agents comprised of adalimumab, etanercept, infliximab, certolizumabpegol, and golimumab. These recommendations also included various vaccinations during the administration of the aforementioned DMARDs. The vaccinations involved pneumococcal, influenza, hepatitis, human papillomavirusas well as herpes zoster vaccines (Singh et al 2012, pg. 627). Since this report has been revised from a similar report in 2008, it serves to reveal the various developments that are constantly taking place in administration of DMARDs and other biological agents used as therapeutic strategies for the treatment of rheumatoid arthritis. Thus, anti-inflammatory drugs have always been preferred to the mediation of MMPs. One of the therapeutic strategies involves the cytokine blockade strategies by the inflammatory TNF α, which has been quite successful. Others include the inhibition of Interleukin -1 (IL-1) by a recombinant IL-1. Anti-IL-6 therapy is a third option in which an antibody is used to block the receptor. Cytokine mediation can be used as a therapeutic device which is known as acute-phase reactant serum amyloid A (Bleavins, 2010). The mediation with these cytokines serves to reduce the inflammatory effects brought about by chronic rheumatoid arthritis and thus serve in relieving pain. It is also targeted therapeutic cytokine intervention that in turn highlights the use of cytokines as diagnostic markers. In this case, it is a cycle of events, each leading to and benefitting the other where disease markers are concerned. MMP-3 is a proteolytic enzyme which is produced as a part of the inflamed joint and thus is classified as a proteolytic enzyme. It destroys synovial tissue in a person with rheumatoid arthritis and therefore may be deemed a systemic marker. The building possibility that MMP-3 can be used as a target for drugs seems hopeful to researchers and scientists alike. Simultaneously, physicians, scientists and researchers are baffled by the results that do not predict MMP-3 as a characteristic marker, specifically for joint destruction in rheumatoid arthritis(Mamahera et al 2010, pg.99). However, it was also revealed in the same study that patients who were treated with non-biological DMARDs showed lesser progressiveness and fewer MMP-3 markers. This paradox baffles and perhaps creates quite a dilemma for the scientists to come up with a better drug that initiates better response and increases quality of life in patients with rheumatoid arthritis. It is interesting to note that these metalloproteinases are not just being looked into and under so much research only to cure the symptoms of rheumatoid arthritis. Takaishi’s investigation explains how they have been under the scrutiny of scientists for the past thirty years. Various inhibitors of matrix metalloproteinases have been pursued to support other diseases the MMPs mediate, such as certain cancer and cardiovascular diseases. But various clinical trials have been held and failed due to certain other shortcomings such as problems with the musculo-skeletal system including bone and muscle pain, inflammation of tendons and many other side effects of non-specific MMP inhibitors. The most challenging aspect seems to be for the scientists to evaluate the pharmacological effects of such inhibitors. For instance, the early studies dileanate that most of the broad spectrum MMP inhibitors initiate musculoskeletal drawbacks which further causes joint stiffness and a syndrome known as the musculoskeletal syndrome. The cause of such syndromes and drawbacks is unknown, however by focusing on some other mediator such as MMP-13, the aim is to identify compounds that can only affect MMP-13, but not other collagenases, so that the negative effects may not resurface, at all (Takaishi et al 2008, pg. 51, 52). Thus, it can be postulated that even though MMPs have been discovered and discussed about to a large extent, they still are in their initial stages of discovery. This paradox is aided by the fact that even though it is evident that MMPs, specifically MMP-3 is acting as a potent mediator of inflammation and displaying itself across all the scans, the information alone is not enough. MMP-3 needs to be further monitored in more populations, amidst a controlled environment so that the results of the undertakings can make significant difference. This difference would in turn lead to a much quicker and easy diagnosis. If the queries regarding matrix metalloproteinases can be solved via further experiments, designing drugs to combat this sort of an inflammation would not be as difficult, as all it would require would be the inhibition of the particular MMP. Furthermore, MMPs other than MMP-3 should be looked into. Perhaps MMPs besides MMP-3 and MMP-13 also play pivotal roles in rheumatoid arthritis and can be dealt with, specifically in order to produce better results and enhance the efficacy of potential drugs that are created. In conclusion, it would best be said that rheumatoid arthritis is a disease which makes the worse of conditions worst by proliferating to drastic stages. It is a disease without cure therefore the sooner it is evaluated, the better. Moreover, even though it is well established that MMP-3 is an integral part of proliferation, diagnosis and therapeutic strategy of rheumatoid arthritis, further research is required in order to make the results tangible and turn the various hypothesis into one substantial rule of thumb to be followed by all. If proper discoveries are made, they would perhaps lead to an improvement in the quality of life for all the rheumatoid arthritis patients. References BLEAVINS, M. R. (2010). Biomarkers in drug development: a handbook of practice, application, and strategy. Hoboken, N.J., John Wiley & Sons. CLARK IM, SWINGLER TE, SAMPIERI CL, & EDWARDS DR. (2008).The regulation of matrix metalloproteinases and their inhibitors. The International Journal of Biochemistry & Cell Biology. 40, 6-7. COLUMBUS, F. H. (2005). Arthritis research: treatment and management. New York, Nova Science Publishers. FRONTERA, W. R., SILVER, J. K., & RIZZO, T. D. (2008). Essentials of physical medicine and rehabilitation: musculoskeletal disorders, pain, and rehabilitation. Philadelphia, PA, Saunders/Elsevier. GREEN MJ, GOUGH AK, DEVLIN J, SMITH J, ASTIN P, TAYLOR D, & EMERY P. (2003). Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis. Rheumatology (Oxford, England). 42, 83-8. HARRIS, ED JR. (1990). Rheumatoid arthritis.Pathophysiology and implications for therapy. The New England Journal of Medicine. 322, 1277-89. HERMAN, J. H. (1973). Rheumatoid arthritis: theoretical and clinical aspects. New York, MSS Information Corp. MAMEHARA A, SUGIMOTO T, SUGIYAMA D, MORINOBU S, TSUJI G, KAWANO S, MORINOBU A, & KUMAGAI S. (2010). Serum matrix metalloproteinase-3 as predictor of joint destruction in rheumatoid arthritis, treated with non-biological disease modifying anti-rheumatic drugs. The Kobe Journal of Medical Sciences. 56, 98-107. NIJKAMP, F. P., & PARNHAM, M. J. (2005).Principles of immunopharmacology. 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