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 E(373) downward arrow(374)A 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-1 alpha. 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
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 6 Pg. 1627-36 (Jun 2007) ISSN: 0021-9738 [Print] United States
PMID	17510707 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Aggrecans DNA Primers Recombinant Proteins Endopeptidases aggrecanase
Topics	Aggrecans (chemistry, genetics, metabolism) Animals Arthritis, Experimental (genetics, metabolism, pathology) Base Sequence Binding Sites (genetics) Cartilage (metabolism, pathology) DNA Primers (genetics) Endopeptidases (metabolism) Female Male Mice Mice, Inbred C57BL Mice, Mutant Strains Mutagenesis Protein Structure, Tertiary Recombinant Proteins (chemistry, genetics, metabolism)

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