Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair
Christopher B. Little, … , Susan M. Smith, Amanda J. Fosang
Christopher B. Little, … , Susan M. Smith, Amanda J. Fosang
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1627-1636. https://doi.org/10.1172/JCI30765.
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Research Article Bone Biology

Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair

Abstract

Aggrecan loss from cartilage in arthritis is mediated by aggrecanases. Aggrecanases cleave aggrecan preferentially in the chondroitin sulfate–2 (CS-2) domain and secondarily at the E373↓374A bond in the interglobular domain (IGD). However, IGD cleavage may be more deleterious for cartilage biomechanics because it releases the entire CS-containing portion of aggrecan. Recent studies identifying aggrecanase-2 (ADAMTS-5) as the predominant aggrecanase in mouse cartilage have not distinguished aggrecanolysis in the IGD from aggrecanolysis in the CS-2 domain. We generated aggrecan knockin mice with a mutation that rendered only the IGD resistant to aggrecanases in order to assess the contribution of this specific cleavage to cartilage pathology. The knockin mice were viable and fertile. Aggrecanase cleavage in the aggrecan IGD was not detected in knockin mouse cartilage in situ nor following digestion with ADAMTS-5 or treatment of cartilage explant cultures with IL-1α. Blocking cleavage in the IGD not only diminished aggrecan loss and cartilage erosion in surgically induced osteoarthritis and a model of inflammatory arthritis, but appeared to stimulate cartilage repair following acute inflammation. We conclude that blocking aggrecanolysis in the aggrecan IGD alone protects against cartilage erosion and may potentiate cartilage repair.

Authors

Christopher B. Little, Clare T. Meeker, Suzanne B. Golub, Kate E. Lawlor, Pamela J. Farmer, Susan M. Smith, Amanda J. Fosang

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Figure 7

Cartilage repair in Jaffa mice.

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Cartilage repair in Jaffa mice. (A–F) Representative toluidine blue–stai...
(A–F) Representative toluidine blue–stained sections of AIA joints from wild-type (A–C) or Jaffa (D–F) cartilage at day 28. A and D show no evidence of repair at day 28. Note the complete loss of toluidine blue in the articular cartilage (asterisks). Repair in wild-type (B and C) and Jaffa mice (E and F) at day 28 was seen predominantly in the femur. F, femoral surface; T, tibial surface. Arrowheads in C point to pericellular staining. Images in C and F are higher magnifications of the same sections shown in B and E. Scale bars: 100 μm. (G) Repair index, calculated as improvement in cartilage aggrecan loss score between days 7 and 28, in wild-type (n = 49; white bar), Chloe (n = 19; black bar), and Jaffa (n = 21; gray bar) femorotibial sections. Results are mean ± SEM. *P < 0.05.