RESEARCH - 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 OA

April 5, 2005

Rheumawire

Janis

, Australia, and Cambridge, MA - A pair of papers in the March 31,

2005 issue of Nature establishes that the aggrecanase ADAMTS5 is the prime

cause of cartilage destruction in animal models of both osteoarthritis (OA)

and rheumatoid arthritis (RA) and that knocking out this single protein

dramatically reduces cartilage deterioration in vivo. [1,2]

Enzymes that contribute to the breakdown of aggrecan have long been an

object of research interest because aggrecan and type 2 collagen together

provide 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 bone

therapeutic research. " We created a mouse with inactive ADAMTS5

(aggrecanase-2), and these mice did not develop osteoarthritis after

surgical induction of joint instability. This is the first report in the

literature of a single gene deletion that affected the course of

osteoarthritis, " tells rheumawire.

The researchers first made ADAMTS5 knockout mice, then caused unilateral

joint instability by surgically transecting the medial meniscotibial

ligament 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 few

weeks. Mice were sacrificed at 4 and 8 weeks after surgery, and joint damage

scores were compared.

The ADAMTS5 knockout mice had significantly less cartilage damage than the

wild-type mice at both time points. Furthermore, when the researchers

cultured bits of femoral head articular cartilage with proinflammatory

modulators IL-1alpha and retinoic acid, those from wild-type mice showed a

significant increase in release of total proteoglycan, a sign of cartilage

degradation, 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 therapeutic

strategy.

" ADAMTS5, or aggrecanase-2, is an enzyme made by chondrocytes that causes

degradation of aggrecan during pathologic joint disease. The goal of a

therapeutic intervention would be inhibition of this enzyme with a small

molecule taken orally, " says .

says that the researchers were surprised to find that ADAMTS5 appears

to be the only enzyme involved in aggrecanase-mediated destruction of

aggrecan 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 OA

is ADAMTS5, as pathogenic mechanisms in mice do not always directly

translate to the human condition, " warns.

ADAMTS5 knockout also protects joints in RA mice

Dr J Fosang led the University of Melbourne (, Australia)

& (San Diego, CA) researchers who reported that deleting

ADAMTS5 also prevents cartilage damage in a mouse model of RA

(antigen-induced arthritis).

" We now know exactly which enzyme is involved in destroying cartilage in

arthritic diseasewhether it be osteo- or inflammatory arthritis. The big

advance here is that now the drug companies know what it is they are trying

to inhibit, and they will be able to take a more targeted approach to

designing inhibitors, " Fosang tells rheumawire.

The Melbourne group established that ADAMTS5 is the major aggrecanase in

mouse cartilage, both in vitro and using the antigen-induced arthritis model

of inflammatory arthritis.

Both Fosang and suspect that targeting ADAMTS5 is likely to be highly

effective in OA and necessary but not sufficient in RA. Fosang points out

that severe, end-stage inflammatory arthritis is associated with the

generation of matrix metalloproteinase (MMP)-derived aggrecan fragments, so

the MMPs are also important.

" It is likely that ADAMTS5 is involved in final cartilage destruction in

both OA and RA, although inhibition of aggrecanase alone would probably have

less beneficial effect in RA because of all the other destructive

inflammatory mechanisms at play, " adds.

Wyeth and other pharmaceutical companies have been hot on the track of

aggrecanase inhibitors for several years. Most efforts have focused on

inhibitors that block the activity of already-activated ADAMTS5, but Fosang

suggests another strategy. " Another angle is to look at how the enzyme is

activated, and this is where we are going, " she says. " It may be more

effective to block activation, rather than try to block the actions of an

already-active enzyme. "

Sources

Glasson SS, Askew R, Sheppard B, et al. Deletion of active

ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis.

Nature 2005; 434:644-648.

Stanton H, on FM, East CJ, et al. ADAMTS5 is the

major aggrecanase in mouse cartilage in vivoand in vitro. Nature 2005;

434:648-652.

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org