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Chuanju Liu, PhD, winner of the Kappa Delta Young Investigator Award, celebrates with colleagues at the NYU Hospital for Joint Diseases. (From left) Dr. Liu, Xiaohui Bai, David Wang, Edward Lin, and Marc Fajardo.

AAOS Now

Published 3/1/2008
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Eileen Norris

Award recognizes cartilage breakdown discovery

Young Investigator Award goes to Chuanju Liu, PhD, and associates

At the 2008 Annual Meeting, the Kappa Delta Young Investigator Award was presented to Chuanju Liu, PhD; Yi Luan, MD, PhD; Yan Zhang, MD, PhD; Ronald Damani Howel, research assistant; and Li Kong, MD, PhD—all from the NYU Hospital for Joint Diseases—for their manuscript, “Two Novel Cartilage-Degrading Metalloproteinases.”

The team identified two new molecules (ADAMTS-7 and ADAMTS-12) associated with the degradation of cartilage and discovered two inhibitors that could potentially slow down or block disease progression. These findings could improve our understanding of the degradative events that occur in patients with arthritis—and perhaps even offer future treatment.

The study presents evidence that both ADAMTS-7 and ADAMTS-12 are significantly elevated in patients with arthritis and that alpha-2 macroglobulin (α2M) and granulin/epithelin precursor (GEP) are naturally occurring inhibitors of ADAMTS-7 and ADAMTS-12. An important potential clinical impact of this research will be to recruit inhibitors of ADAMTS-7 and ADAMTS-12 or their analogous compounds to devise a novel treatment for arthritic disorders. These two enzymes could also be used as novel biomarkers for arthritis disorders, Dr. Liu added.

Earlier research
Loss of articular cartilage due to extracellular matrix breakdown is the hallmark of arthritis; researchers have observed fragments of cartilage oligomeric matrix protein (COMP) in patients with arthritis. The molecular mechanism of COMP degradation and the enzyme(s) responsible for it, however, have remained largely unknown.

Dr. Liu and his colleagues previously had reported that ADAMTS-7 and ADAMTS-12 were able to degrade COMP. Now, they point to the following three new discoveries:

  • The size of COMP fragments produced by either ADAMTS-7 or ADAMTS-12 is similar to that of COMP-degradative fragments seen in patients with osteoarthritis (OA).
  • Specific antibodies against ADAMTS-7 or ADAMTS-12 dramatically inhibit COMP degradation induced by tumor necrosis factor-alpha and by interleukin 1-beta in cultured cartilage explants.
  • Suppression of ADAMTS-7 or ADAMTS-12 expression using the siRNA silencing approach in human chondrocytes also markedly prevents COMP degradation.

Furthermore, researchers found that α2M, a protein found in plasma, is a substrate for ADAMTS-7 and ADAMTS-12 and inhibits both ADAMTS-7- and ADAMTS-12-mediated COMP degradation. More significantly, GEP growth factor associates with ADAMTS-7 and ADAMTS-12, disturbs the interactions between COMP and ADAMTS-7/-12, and efficiently prevents COMP degradation mediated by ADAMTS-7/-12. Together, these findings indicate that ADAMTS-7 and ADAMTS-12 are two novel enzymes responsible for COMP degradation in arthritis and that α2M and GEP represent their endogenous inhibitors.

Mounting evidence
“We found that ADAMTS-7 and ADAMTS-12, which have similar domain organization and structure, associated with and cleaved COMP and that their levels were significantly elevated in the cartilage of arthritis patients,” said Dr. Liu.

“We also showed that an additional fragment was observed in OA samples that was absent in ADAMTS-12- and ADAMTS-7-mediated COMP digestion, suggesting that additional enzyme(s) may also contribute to COMP degradation in OA patients,” the researchers wrote.

Therefore, in contrast to α2M, which has been shown to inhibit the activity of several enzymes, GEP may represent a specific inhibitor of ADAMTS-7 and ADAMTS-12 cleavage of COMP. Whether and how ADAMTS-7 and ADAMTS-12 regulate GEP activity remains to be delineated, said the authors.

Summary findings
“Identifying ADAMTS-7 and ADAMTS-12 as two novel cartilage-degrading enzymes, recognizing their importance for the in vivo degradation of cartilage, the isolation of α2M and GEP as novel substrates for ADAMTS-7 and ADAMTS-12, and the subsequent characterization of their inhibition of ADAMTS-7 and ADAMTS-12 all serve to significantly extend our understanding,” said Dr. Liu. “Now we know more about the degradative events that occur in joint disorders, all of which promises to increase our ability to monitor the biological and physical properties of cartilage extracellular matrix in the future.” These findings provide promising therapeutic targets for treating cartilage disorders, including osteoarthritis, he added.

“We can’t reverse the disease,” said Dr. Liu, “but if we’re lucky we may find compounds to interrupt the progression of arthritis. The patient will benefit if we can slow down progression of the disease. Next, we will try to identify smaller peptides based on the inhibitors for cost-effective therapy. That’s the goal.”

The primary investigator’s research was supported by the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute on Aging, the Arthritis Foundation, the Arthritis National Research Foundation, and the Department of Orthopaedic Surgery of New York University. Dr. Liu has no commercial or consulting relationships with any medical, orthopaedic, or device manufacturer.

Eileen Norris is a freelance writer specializing in healthcare issues.