ADAMTS4 and ADAMTS5 Knockout Mice Are Protected from Versican but Not Aggrecan or Brevican Proteolysis during Spinal Cord Injury

Abstract

The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50–60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4−/−, Adamts5−/−, and wt mice but not in the sham-operated group. By contrast Adamts4−/− and Adamts5−/− mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4−/− mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4−/− or Adamts5−/− mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.

Chondroitin 6-Sulfation Regulates Perineuronal Net Formation by Controlling the Stability of Aggrecan

“…ADAMTS-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) have been proposed to be responsible for aggrecan degradation [ 20 ]. However, recent study using ADAMTS-4 and ADAMTS-5 knockout mice suggested the presence of additional aggrecan-degrading enzymes in the spinal cord [ 24 ]. In the cerebral cortex, ADAMTS-8 and ADAMTS-15 are exclusively expressed by PV-cells, which are surrounded by PNNs [ 25 , 26 ], suggesting that these may be novel aggrecan-degrading enzymes specifically involved in turnover and remodeling of PNNs in vivo .…”

Proteolytic Remodeling of Perineuronal Nets: Effects on Synaptic Plasticity and Neuronal Population Dynamics

“…There may, however, be a regional specificity regarding ADAMTS-dependent cleavage of brevican given the lack of colocalization between WFA-labeled PNNs and ADAMTS-derived brevican cleavage fragments in the rodent brain [ 60 ]. Additionally, the role of other enzymes in aggrecan and brevican proteolysis cannot be ruled out since cleavage products of both proteins are detected in Adamts-4 −/− and Adamts-5 −/− mice following spinal cord injury [ 61 ]. In contrast, versican cleavage is not observed in either knockout mouse following injury [ 61 ].…”

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…Surgically induced OA experiments performed in both ADAMTS4 and ADAMTS5 knockout mice showed that deletion of the ADAMTS5 gene alone relieved cartilage degradation, while deletion of the ADAMTS4 gene could not (64), suggesting that ADAMTS5 may play a more important role in OA development than ADAMTS4. In fact, study of ADAMTS5 knockout mice showed that the protection was due to elimination of fibrous overgrowth from the periarticular tissues and deposition of newly synthesized aggrecan in the cartilage (65). The effect of ADAMTS5 on collagenous tissues may be revealed by an analysis of Smad-signaling pathways in wild-type and ADAMTS5-deficient fibroblasts and chondrocytes.…”