ADAMTS Proteases and Their Roles in Joint Tissues
First identified in 1997, ADAMTS proteases have been associated with a number of different diseases and are of high biomedical relevance. Proteases are molecules that “cut up” proteins into two or more smaller components. The process of cutting up large protein molecules is called proteolysis and is an essential housekeeping task in such musculoskeletal tissues as muscle, bone and connective tissues, which undergo constant wear and tear, breakdown and rebuilding. This remodeling process is particularly active during growth and development, inflammation, alterations in bone density such as in osteoporosis, disuse of connective tissues, and during cartilage destruction in arthritis.
ADAMTS Family Members
The nineteen different ADAMTS proteases are specialists, that is, they cut only certain molecules and they cut them at very specific sites. These products of proteolysis may then be used in other cellular functions or may be cleared from the body. In fact, many of the body’s normal functions require that precursor proteins undergo proteolysis before they become fully functional. The best example of this in musculoskeletal tissues is collagen, which is made by cells as a non-functional precursor called procollagen. The ends are then snipped off by proteases (one end is snipped off by specialized ADAMTS proteases) to allow it to function well. Genetic mutations in the proteases that do this cause severe connective tissue disorders.
Suneel S. Apte, MBBS, DPhil, of the Cleveland Clinic Foundation in Ohio, has received a grant from the Northeastern Ohio Chapter of the Arthritis Foundation to study members of this family of proteases that are relevant to arthritis. Several ADAMTS proteases and the related ADAMTS-like proteins were discovered or first characterized by his laboratory.
ADAMTS and Cartilage
Taken together with the work of several other research groups working on ADAMTS proteases all over the world, there has been much progress in understanding what ADAMTS proteases do in the joints and related musculoskeletal tissues. This family of proteases is now a major area of significance in arthritis and musculoskeletal research.
ADAMTS5 and ADAMTS4 have been identified as the major culprits responsible for destruction of cartilage aggrecan in arthritis. Cartilage aggrecan, together with the specialized collagen present in cartilage, provides it with the ability to resist mechanical loads. In arthritis, first the aggrecan and subsequently the collagen are lost. One of the major activities in Dr. Apte’s group is identifying what the normal functions of these proteases might be, so that in efforts to target them for prevention of cartilage degradation, the potential side effects may be understood and avoided. Many years ago, in work also supported by the Arthritis Foundation through an Arthritis Investigator award, Dr. Apte made a number of contributions to the understanding of TIMP3, a protease inhibitor, which today is being looked at as a possible treatment for arthritis because it is a good inhibitor of ADAMTS4 and ADAMTS5.
Dr. Apte’s Current Grant
The two-year Northeastern Ohio Chapter grant specifically supports studies on ADAMTS7, which is present in developing muscle, bone and cartilage and is known to cleave COMP, a protein present in cartilage. ADAMTS7 was first discovered in Dr. Apte’s lab and the initial discovery was accompanied by the realization that, unlike any other protease, it was coated with chondroitin sulfate, which was especially unusual and suggested this enzyme was highly specialized. The current studies have identified the points along the protease at which chondroitin sulfate is attached and are now asking what the effect of removing the chondroitin sulfate will be. In addition, the work has revealed that developing musculoskeletal tissues, especially muscle, are highly enriched in ADAMTS7. The main question being asked now is what this protease does, so the laboratory is attempting to identify additional protein targets.
In studies supported by the National Institutes of Health, Dr. Apte’s research team studies the role of ADAMTS10 in Weill-Marchesani syndrome (a rare, genetic disorder characterized by short stature; unusually short fingers; and distinctive eye abnormalities). Although this syndrome is rare, it is of great interest because it is the opposite of the Marfan syndrome (a relatively common inherited disorder that affects the connective tissue of the heart, blood vessels, musculoskeletal system and eyes, resulting in unusual height and long fingers and toes; especially of concern, the syndrome also causes a propensity to expansion and rupture of the aorta). Earlier, Dr. Apte’s group had shown that ADAMTS3 was likely to be responsible for the maturation of collagen in cartilage and bone and had provided new insights on the clinical features of one of the Ehlers-Danlos syndromes (a group of hereditary connective tissue disorders characterized by collagen defects). Recently, the group has determined that ADAMTS9 and ADAMTS20 have a major role in allowing the palate to form normally, since a defect in these enzymes in mice leads to cleft palate, which is one of the commonest human birth malformations.
Importance of Basic Research
The kind of basic science research undertaken by Dr. Apte’s lab usually gets little recognition or publicity because its potential effect on disease is sometimes hard to imagine, and because the scientific and technical details are often unglamorous. However, it is the knowledge gained through these fundamental inquiries that opens doors, leads to new questions and more discoveries that may be translated into diagnostic biomarkers or disease cures. Without understanding the elemental roots of disease and the ins and outs of how molecules work, successful treatments and potential cures may be harder to come or may be based on incomplete knowledge. Dr. Apte emphasizes that the support and encouragement he received from the Arthritis Foundation early in his career allowed him to take the critical steps to becoming an independent investigator, and have motivated him to continue working in areas of interest to the Foundation. Additionally, the funding received by his group supports the training of students and postdoctoral fellows and ensures that future generations of scientists will continue to be involved with the problems of arthritis.