The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury

Abstract

Background: Chondroitin sulfate proteoglycans are major inhibitory molecules for neural plasticity under both physiological and pathological conditions. The chondroitin sulfate degrading enzyme chondroitinase ABC promotes functional recovery after spinal cord injury, and restores experience-dependent plasticity, such as ocular dominance plasticity and fear erasure plasticity, in adult rodents. These data suggest that the sugar chain in a proteoglycan moiety is essential for the inhibitory activity of proteoglycans. However, the significance of the core protein has not been studied extensively. Furthermore, considering that chondroitinase ABC is derived from bacteria, a mammalian endogenous enzyme which can inactivate the proteoglycans' activity is desirable for clinical use.

Low Density Lipoprotein Receptor-related Protein 1 (LRP1)-mediated Endocytic Clearance of a Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4)

“…The expression of ADAMTS-4 and ADAMTS-5 mRNAs has been reported to increase in human glioblastomas (41)(42)(43) and ADAMTS-4, and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice (44). Interestingly, ADAMTS-4 pro- motes neurite outgrowth by cleaving proteoglycans, which contributes to functional recovery after spinal cord injury (45). Thus, LRP1-mediated endocytosis of ADAMTS-4 may play a regulatory role in tumor malignancy and neurite outgrowth.…”

Pathophysiology of the brain extracellular matrix: a new target for remyelination

“…ADAMTSs are less neurotoxic than MMPs (M.B.K., L.W.L., R.C. and V.W.Y., unpublished observations), and the local delivery of ADAMTS4 to rodents with traumatic spinal cord injury has improved motor recovery 61 . Whether this involved ECM remodelling is unknown.…”

Pathophysiological Function of ADAMTS Enzymes on Molecular Mechanism of Alzheimer’s Disease

“…However, expression level of ADAMTS4 was not altered in this report. Another study demonstrated both increased ADAMTS4 protein and aggrecan cleavage following SCI [58]. ADAMTS were detected in the astrocytes implying its cellular source in SCI by means of immunohistochemistry.…”

“…Proteolysis of proteoglycans by ADAMTS enzymes can have destructive effects, producing matrices with disrupted cell-matrix communication, matrices with impaired fibrillary networks, or matrices with altered biomechanical properties [11]. After numerous comprehensive studies, ADAMTS expression has been found in the CNS [49][50][51][52][53][54][55][56][57][58][59][60] and is known to be changed in disease conditions [44,51,53].…”

“…Roles of ADAMTS proteoglycanases in CNS are suggested to be both physiological and pathological such as neuroplasticity, inflammation, regeneration, remyelination, neurorepair (CSPGs degradation), and angiogenesis [61]. Recent studies indicate that expression level of ADAMTS and CPGs may be change after spinal cord injury in animal models [58,59,60]. Demircan et al [60] reported that ADAMTS1, -5 and -9 expression levels were found to be upregulated following spinal cord injury (SCI) in mouse.…”