MMPs role in arthritic diseases

Matrix Metalloproteinases (MMPs) are enzymes considered to be responsible for cartilage bone damage. There are over 20 zinc-containing endopeptidases that include collagenases, gelatinases, stromelysins. MMPs are released as inactive but become active only when the propeptide is cleaved. MMPs have a key role in normal connective tissue remodeling and their activation, release, and inhibition (by TIMPs) is tightly regulated. Because they can degrade all components of the extracellular matrix, they have been implicated in numerous pathological conditions.The capacity of chondrocytes to degrade components of extracellular matrix depends on their ability to produce and secrete proteinases. They can be produced in response to IL-1, IL-17, IL18 and TNF which are found in excess in arthritic joints. Expression and production of proteinases (MMPs) is increased in OA and RA as well as other diseases.
In the article "Cytokines in the pathogenesis of rheumatoid arthritis" two mechanism lead to the disintegration of undifferentiated cartilage. Chondrocytes switch from an anabolic matrix-synthesizing state to a catabolic state. This state is chacterized by the formation of ADAMTs (a desintegrin and metalloproteinase) and MMPs that cleave the cartilage component of proteoglycan and collagen fivers. Synovial fibroblast also release MMPs, neutrophils and potentially mast cells, which are closely located to articular cartilage and can effect the damaging process.
IL-1β plays a central role in cartilage degradation through prevention of matrix synthesis as well as through induction of the matrix-degrading enzymes MMP1, MMP3, MMP8, MMP13, and MMP14.
IL-1-driven animal models of arthritis such as cartilage induced arthritis show rapid and extensive cartilage damage. Injection of IL-1 intra-articular led to PG loss, chondrocyte apoptosis and matrix degradation. Injection of IL-17 increased PG loss but did not progess to erosion and death of chondrocytes. Upon induction of CIA (cartilage induced arthritis), exogenous IL-17 worsened cartilage damage and led to erosion and death of chondrocytes. Therefore, IL-17 can act independently and synergistically with IL-1β and TNF to promote cartilage degradation. IL-18 also promotes cartilage degradation via IL-1 β.
In the article Molecular aspects of pathogenesis in osteoarthritis: the role of inflammation, higher concentrations of MMPs as well as elevated levels of tissue inhibitor of MMPs (TIMPs) were found in synovial fluid compared to healthy controls in an attempt by chondrocytes to balance excessive proteinase activity.
Overexpression of MMP-13 has been found in patients with OA. MMP-13 preferentially degrades collagen II. MMP-12 expression in macrophages significantly exacervate the development of experimental inflammatory arthritis in transgenic rabits.
Recent studies have shown the presence of selective collagenase inhibitors against MMP-13 and MMP-8 (in cultured OA) to halter the cleavage of collagen II. MMP-3 synthesis and inhibition of TIMP-1 production have been linked to apoptotic and antiproliferative catabolic effects. Very interesting studies are being done with MMP inhibitors. Some results have not been satisfactory mainly because of its toxic side effects and lack of enzyme specificity.

Other references:
MMP12, an Old Enzyme Plays a New Role in the Pathogenesis of RA?
Matrix metalloproteinase inhibitors in rheumatic diseases.
Matrix metalloproteinase 9 (MMP9) gene polymorphism and MMP-9 plasma levels in primary Sjogren's syndrome - did not discuss but very interesting.

Arthritis and current drug treatments

After class I was interested in what drugs were currently being used for the treatment of RA and how they worked. I work in a pharmacy and spoke with one of my pharmacists. He said that usually corticoids are usually used first, primarily because they are less expensive. Next in line are DMARDS, disease-modifying antirheumatic drugs. Common ones are methotrexate, hydrochloroquine, among others. Then after those are used anticytockines are used. There are two antibody drugs humira and remicade. Humira deals with TNF alpha. Embral is a "fake" TNF alpha receptor. So the TNF alpha will bind to it and hopefully be able to be stopped. Kineret is a drug that deals with the IL-1. He also mentioned that it would be uncommon for a doctor to prescribe a drug that would deal with IL-1 first because they are so expensive and its unlikely that an insurance would want to pay for one of them before something less expensive.

Degenerative and Glucosamine...

The paper “Enhanced and Coordinated in Vivo Expression of Inflammatory Cytokines and Nitric Oxide Synthase by Chondrocytes from Patients with Osteoarthritis” was quite interesting because it compared the inflammatory activity at arthritic joints from two sources—the synovial membrane and the cartilage within the joint. The paper divides the four test arthritises, rheumatic, psoriatic, osteoarthritis and traumatic knee arthritis into two groups of arthritic disease—inflammatory (RA and PsA) and degenerative (traumatic and OA). One small point that caught my eye was the concluding sentence of the paper “both inflammatory and so-called degenerative arthropathies” (2173). It caught my eye because for one it seemed very out of tone with the rest of the paper. However, I decided to look into the degenerative classification. One article I found, the “International Symposium on ‘Joint Failure’: Recent Advances in Osteoarthritis and related Disorders,” commented that “the term ‘degenerative’ implied irreversible pathological changes” and the fact that cartilage used to be seen as a metabolically dead tissue gives rise to the idea that osteoarthritis is a degenerative disease. However, as we know cartilage and chrondocytes is very metabolically active and I thought it was interesting that “matrix synthesis is osteoarthritic joints is actually greater than in normal joints and increases with the severity of the disease”

On a different note, when I was surfing the net about osteoarthritis, a site with health supplements to reduce osteoarthritic symptoms came up. Glucosamine is currently classified in the US strictly as a health supplement. It is said to be affective due to its anti-inflammatory effects, stimulation of proteoglycan synthesis and by decreasing the metabolic activity of chrondocytes. However its drug trial history has given opposing and contradictory results, also it should be note initial trials were sponsored by the paten holder of the drug—interestingly enough the initial trials were all reported successful. While the drug is medically approved for use in Europe, it is still undergoing testing and trial by the National Health Institute in the US. The trial mentioned in an article online is called Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). I think it is interesting that the paper we read commented that the “succession of events in the pathogenesis of OA” is elusive yet drugs are being researched and used without really knowing the ramifications since the actual pathway within the body is still relatively unknown.

”International Symposium on ‘Joint Failure’: Recent Advances in Osteoarthritis and related Disorders” British Journal of Rheumatology

http://rheumatology.oxfordjournals.org/cgi/reprint/23/3/166.pdf

Efficacy of Glucosamine and Chondroitin Sulfate May Depend on Level of Osteoarthritis Pain

http://www.nih.gov/news/pr/feb2006/nccam-22.htm

CNS can control Arthritic Joint Inflammation and Destruction

Researchers from the University of California, San Diego are experimenting with targeting the central nervous system in an attempt to control immune and inflammation response in RA and OA. Using a rat model with RA, they found the could successfully decrease inflamation and destruction of joint tissue by injecting substances into the spinal cord thereby inhibiting the signal from the brain that induces inflammation and immune response. The basis for this is simple. By inhibiting immune signals from the brain, inflammation and destruction in the joints should decrease. The only problem I find with this is isolating a specific pathway and not affecting another. It is known that many physiological signaling pathway cross-talk with one another.
They inhibited TNF alpha, which is responsible for the continuious and ongoing symptoms involved in the desctruction of joint tissue, and found that sypmtoms decreased. However, TNF alpha has many roles in other instances of inflammation and immune response. These other "roles" can ultimately be inhibited and cease to protect and organism from potential harm from disease and in instances were the inflammatory response and immunce response is critical.