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.