Blocking a single protein might stop cartilage destruction in both RA and OA

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Blocking a single protein might stop cartilage destruction in both RA and OAApril 5, 2005RheumawireJanis , Australia, and Cambridge, MA - A pair of papers in the March 31,2005 issue of Nature establishes that the aggrecanase ADAMTS5 is the primecause of cartilage destruction in animal models of both osteoarthritis (OA)and rheumatoid arthritis (RA) and that knocking out this single proteindramatically reduces cartilage deterioration in vivo. [1,2]Enzymes that contribute to the breakdown of aggrecan have long been anobject of research interest because aggrecan and type 2 collagen togetherprovide cartilage its characteristic toughness and elasticity.Route to a DMARD for osteoarthritis?The osteoarthritis study was by Wyeth scientists led by Dr beth ,director of the company's osteoarthritis, women's health, and bonetherapeutic research. "We created a mouse with inactive ADAMTS5(aggrecanase-2), and these mice did not develop osteoarthritis aftersurgical induction of joint instability. This is the first report in theliterature of a single gene deletion that affected the course ofosteoarthritis," tells rheumawire.The researchers first made ADAMTS5 knockout mice, then caused unilateraljoint instability by surgically transecting the medial meniscotibialligament in a group of these mice and in a control group of wild-type mice.This model typically produces OA-like cartilage deterioration within a fewweeks. Mice were sacrificed at 4 and 8 weeks after surgery, and joint damagescores were compared.The ADAMTS5 knockout mice had significantly less cartilage damage than thewild-type mice at both time points. Furthermore, when the researcherscultured bits of femoral head articular cartilage with proinflammatorymodulators IL-1alpha and retinoic acid, those from wild-type mice showed asignificant increase in release of total proteoglycan, a sign of cartilagedegradation, but those from ADAMTS5 knockout mice did not. Interestingly,deleting ADAMTS5 did not alter the growth or development of the mice,suggesting that targeting this enzyme might be a viable therapeuticstrategy."ADAMTS5, or aggrecanase-2, is an enzyme made by chondrocytes that causesdegradation of aggrecan during pathologic joint disease. The goal of atherapeutic intervention would be inhibition of this enzyme with a smallmolecule taken orally," says . says that the researchers were surprised to find that ADAMTS5 appearsto be the only enzyme involved in aggrecanase-mediated destruction ofaggrecan in OA mice, as they had suspected that both ADAMTS4 (aggrecanase-1)and ADAMTS5 (aggrecanase-2) were responsible."We will have to work hard to verify that the only aggrecanase in human OAis ADAMTS5, as pathogenic mechanisms in mice do not always directlytranslate to the human condition," warns.ADAMTS5 knockout also protects joints in RA miceDr J Fosang led the University of Melbourne (, Australia) & (San Diego, CA) researchers who reported that deletingADAMTS5 also prevents cartilage damage in a mouse model of RA(antigen-induced arthritis)."We now know exactly which enzyme is involved in destroying cartilage inarthritic diseasewhether it be osteo- or inflammatory arthritis. The bigadvance here is that now the drug companies know what it is they are tryingto inhibit, and they will be able to take a more targeted approach todesigning inhibitors," Fosang tells rheumawire.The Melbourne group established that ADAMTS5 is the major aggrecanase inmouse cartilage, both in vitro and using the antigen-induced arthritis modelof inflammatory arthritis.Both Fosang and suspect that targeting ADAMTS5 is likely to be highlyeffective in OA and necessary but not sufficient in RA. Fosang points outthat severe, end-stage inflammatory arthritis is associated with thegeneration of matrix metalloproteinase (MMP)-derived aggrecan fragments, sothe MMPs are also important."It is likely that ADAMTS5 is involved in final cartilage destruction inboth OA and RA, although inhibition of aggrecanase alone would probably haveless beneficial effect in RA because of all the other destructiveinflammatory mechanisms at play," adds.Wyeth and other pharmaceutical companies have been hot on the track ofaggrecanase inhibitors for several years. Most efforts have focused oninhibitors that block the activity of already-activated ADAMTS5, but Fosangsuggests another strategy. "Another angle is to look at how the enzyme isactivated, and this is where we are going," she says. "It may be moreeffective to block activation, rather than try to block the actions of analready-active enzyme." Sources Glasson SS, Askew R, Sheppard B, et al. Deletion of activeADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis.Nature 2005; 434:644-648. Stanton H, on FM, East CJ, et al. ADAMTS5 is themajor aggrecanase in mouse cartilage in vivoand in vitro. Nature 2005;434:648-652.