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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Categories: 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 5

DMM model in wild-type and aggrecan knockin mice.

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DMM model in wild-type and aggrecan knockin mice. (A–C) Representative t...
(A–C) Representative toluidine blue/fast green–stained sagittal sections of medial femorotibial joints from wild-type mice demonstrating mild (A), moderate (B), and severe lesions (C). Scale bar: 200 μm. (D) Sum of scores for tibial cartilage structural damage (mean ± SEM) in the medial tibial plateau at 4 or 8 weeks after surgery in wild-type (n = 12 [4 wk], 11 [8 wk]; open bars), Chloe (n = 13 [4 wk], 11 [8 wk]; black bars), and Jaffa (n = 11 [4 wk], 8 [8 wk]; gray bars) joints after DMM induction. **P < 0.01; ***P < 0.001.