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ADAMTS proteoglycanases in the physiological and pathological central nervous system


ADAMTS-1, -4, -5 and -9 belong to ‘a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)’ family and more precisely to the proteoglycanases subgroup based on their common ability to degrade chondroitin sulfate proteoglycans. They have been extensively investigated for their involvement in inflammation-induced osteoarthritis, and a growing body of evidence indicates that they may be of key importance in the physiological and pathological central nervous system (CNS). In this review, we discuss the deregulated expression of ADAMTS proteoglycanases during acute CNS injuries, such as stroke and spinal cord injury. Then, we provide new insights on ADAMTS proteoglycanases mediating synaptic plasticity, neurorepair, angiogenesis and inflammation mechanisms. Altogether, this review allows us to propose that ADAMTS proteoglycanases may be original therapeutic targets for CNS injuries.


The ADAMTS proteases belong to ‘a disintegrin and metalloproteinase with thrombospondin motifs’ family, composed of 19 members. They are multi-domain proteins synthesized as pre-pro-enzymes containing from the N- to the C-terminal end: a peptide signal, a pro-domain, a zinc binding metalloproteinase domain, a disintegrin-like domain, a thrombospondin domain, a cysteine-rich domain, a spacer domain and finally a variable number of thrombospondin motifs in the C-terminal end [1, 2]. Pre-pro-ADAMTS proteases can be cleaved by furin or furin-like proteases at the N- and C-terminal positions triggering, respectively, their activity and their future location within the extracellular matrix (ECM) via the removal of the pro-domain, and their substrate specificity [311]. When secreted, ADAMTS proteases are capable of binding ECM components via their thrombospondin motifs [3], which can be then cleaved by the metalloproteinase domain. ADAMTS proteases are classified in three subfamilies based on their preference to cleave specific ECM macromolecules as follows [1214]: proteoglycans (ADAMTS-1, -4, -5, -8, -9, -15 and -20), pro-collagens (ADAMTS-2, -3 and -14) or the von Willebrand factor (ADAMTS-13). This review will focus on the ADAMTS proteoglycanases present in the central nervous system (CNS), with special emphasis on ADAMTS-1, -4, -5 and -9, which are key enzymes in the degradation of the aggregating chondroitin sulfate proteoglycans (CSPGs) [14].

CSPGs are a family of ECM macromolecules characterized by a core protein and a variable number of glycosaminoglycan chains. The major CSPGs found in the CNS are lecticans (for example, aggrecan, brevican, neurocan and versican), phosphocan and type 2 neuroglycan. They are concentrated into perineuronal nets (PNNs) that enwrap a subset of neurons and control the path finding and guidance of axons during CNS development. After CNS injury, CSPGs are rapidly upregulated within the glial scar and exert both beneficial and deleterious effects. For instance, their contribution to the establishment of a dense glial scar initially constitutes a protective barrier to limit the propagation of damage, but also represents a harmful barrier to subsequent neurorepair and neuroplasticity [15].

While ADAMTS proteoglycanases have been extensively described for their deleterious effect in osteoarthritis, rheumatoid arthritis and vertebral disc degeneration, it is only recently that their role in the CNS has been discussed. Therefore, in this review we will provide up-to-date information about the increasing evidence for the involvement of ADAMTS proteoglycanases in physiological conditions and CNS pathological disease states including ischemic stroke and spinal cord injury (SCI).

ADAMTS proteoglycanases in the physiological central nervous system

ADAMTS proteoglycanases are present in several CNS structures, including the cortex, the hippocampus, the striatum and the spinal cord [1621]. While it is clear that astrocytes express ADAMTS proteoglycanases in vitro and in vivo[2225], their presence in neurons under physiological conditions is controversial. ADAMTS-4 was identified in dentate granule neurons and pyramidal cells by in situ hybridization in rat brains [16]. Similarly, the expression of ADAMTS-4 was described in cortical neurons in vitro[25], but a more recent investigation failed to detect ADAMTS-4 in cerebellar granule neurons in vitro[24]. The presence of ADAMTS-4 has also been reported in cortical microglia in vitro[24, 25] (Table 1).

Table 1 Cellular expression of ADAMTS proteoglycanases in the physiological and pathological central nervous system

In the physiological CNS, evidence exists for a role of ADAMTS proteoglycanases in neural plasticity in vitro and in vivo. Yuan and collaborators were the first to discover evidence of the presence of ADAMTS-1, -4 and ADAMTS-cleaved brevican fragments in the physiological CNS in rats, particularly in plastic regions such as the hippocampus, suggesting the involvement of the ADAMTS proteoglycanases in the malleability of PNNs-containing brevican [16]. Hamel and collaborators (2008) discovered that a recombinant active ADAMTS-4 promoted neurite growth of cortical neurons in vitro i) by degrading CSPGs via its proteolytic activity, and ii) by activating the MAP/ERK (mitogen activated protein/extracellular signal-regulated kinase) signaling pathway, presumably due to the activation of tyrosin kinase receptors by the thrombospondin domain of ADAMTS-4 [26]. However, the concept of CSPGs/ADAMTS proteoglycanases working in concert to regulate plasticity has been explored only recently in vivo[19]. Interestingly, the expression of synaptic proteins, such as synaptosomal-associated protein 25 (SNAP-25), postsynaptic density protein 95 (PSD-95) and synaptophysin, was decreased in the developing frontal cortex of ADAMTS-1 deficient female mice, but not in male mice, suggesting a gender-specific involvement of ADAMTS-1 in synaptic plasticity. However, the decline in expression of synaptic proteins was not accompanied by any modifications of CSPGs present in PNNs, or by deficits of learning and memory [19]. Recently, Krstic and collaborators (2012) proposed ADAMTS-4 and ADAMTS-5 as proteases capable of cleaving Reelin, an extracellular molecule also involved in neurodevelopment and in synaptic plasticity induced learning and memory processes [20]. Interestingly, ADAMTS-induced cleavage of Reelin is thought to partly promote its aggregation during aging, and to participate in the well-known synaptic plasticity defects in elderly CNS tissues [20].

To summarize, ADAMTS proteoglycanases in the physiological CNS are synthesized mainly by astrocytes and expressed in several CNS structures. Interestingly, increasing evidence suggests that they may play critical roles in the control of synaptic plasticity during development and aging via both proteolytic-dependent and -independent mechanisms.

ADAMTS proteoglycanases in the pathological central nervous system

Proteolysis of the ECM can be both beneficial and harmful in several pathological states of the CNS, including ischemic stroke and SCI [27]. A tight control of the local environment is crucial to ensure a moderate remodeling of the ECM in order to promote neuronal plasticity and survival, or vascular remodeling, after acute CNS injuries. While the expression and associated beneficial or deleterious effects of matrix metalloproteinases (MMPs) have been extensively reported in several CNS diseases, recent publications strongly suggest that the ADAMTS proteoglycanases may also be important in ECM proteolysis in CNS injuries.

ADAMTS proteoglycanases: cytokine- and cell-specific inducible proteases

Several cytokines, including IL-1β (interleukin-1β), IL-6, IFN-ɣ (ɣ-interferon), TGF-β (transforming growth factor-β) and TNF-α (tumor necrosis factor-α), have previously been described to regulate the expression of ADAMTS proteoglycanases in non-CNS cell types [2831]. The cytokine-rich environment following CNS injuries is therefore likely to induce the expression of a complex pattern of ADAMTS proteoglycanases in a cell- and cytokine-dependent manner. An increased synthesis of ADAMTS-4, -5 and -9 by astrocytes was reported after transient middle cerebral artery occlusion (tMCAO) [32, 33]. Similarly, injured neurons were described to synthesize ADAMTS-9 after tMCAO [32], but not after contusion-induced SCI [34]. Interestingly, ADAMTS-1 was also specifically upregulated in cerebral motor neurons after peripheral nerve injury [35]. Few cytokines have been already proposed to regulate ADAMTS proteoglycanases expression in the CNS (Table 1). IL-1α in combination with IL-1 receptor type 1 promotes ADAMTS-1 transcription in a N1E-115 neuroblast cell line in vitro and in motoneurons after nerve injury in vivo[35]. ADAMTS-4 mRNA and protein expressions were increased by TNF-α in human astrocyte cultures after 24 hours of treatment, while only upregulation of ADAMTS-1 mRNA or ADAMTS-5 protein levels were reported. Under similar conditions, IL-1β did not regulate the transcription of ADAMTS proteoglycanases, although it seems that there is a trend for an increased mRNA expression of ADAMTS-4 [23]. Beyond astrocytes, microglia and neurons, macrophages that infiltrate brain or spinal cord after injury may also be an important source of ADAMTS-1, -4 and -5 [36, 37]. Interestingly, while TNF-α and IFN-ɣ increase the expression of ADAMTS-4 in macrophages induced by differentiation of human monocytic cell line THP1 [37], TGF-β negatively regulates ADAMTS-4 expression through the MAPK and the Smad-2 and -3 signaling pathways [36]. In similar conditions, it was also described that TGF-β can increase the synthesis of ADAMTS-4 [38].

Accordingly, modification of ADAMTS proteoglycanases expression has been reported after CNS injuries including stroke and SCI (Table 2). Yuan and collaborators were first to discover evidence of the increase of ADAMTS-1, -4 and ADAMTS-cleaved brevican fragments after intraperitoneal injection of kainate-induced CNS excitoxicity, in the cortex and in the hippocampus, by pyramidal neurons and dentate granule neurons [16]. After tMCAO, the expression of ADAMTS-1, -4, and -9 is upregulated [23, 32]. Surprisingly, whereas mRNA changes were observed in the ipsilateral hemisphere acutely at 6 and 24 hours after stroke onset, the upregulation of the protein levels of ADAMTS-1 and -4 was only observed 5 days after injury. Because TNF-α was shown to promote ADAMTS-1 and -4 mRNA levels as well as ADAMTS-4 and -5 protein levels in human astrocyte cultures, it was hypothesized that the increase of TNF-α expression in the acute phase of stroke may be responsible for the upregulation of ADAMTS-1 and -4 by astrocytes [23]. Surprisingly, it is only recently that the upregulation of ADAMTS-4 and -5 mRNA levels were detected in astrocytes after tMCAO in mice 24 hours after stroke onset [33]. The expression of ADAMTS-9 was increased in the acute phase of stroke within 24 hours post occlusion at both the mRNA and protein levels, but rather than astrocytes, neurons were predominantly affected in both contralateral and ipsilateral hemispheres [32]. Similarly, upregulation of ADAMTS-1, -5 and -9 mRNA levels were reported in the acute phase of contusion-induced SCI in mice, whereas no changes to ADAMTS-4 expression were observed [34]. Tauchi and colleagues (2012) detected a slight increase of ADAMTS-4 protein levels associated with a significant increase in ADAMTS-4 enzymatic activity in spinal cord lysates from the lesion site one week after contusion-induced SCI in rats [24]. Demircan and colleagues (2013) also described the astrocytes as being a main source of ADAMTS-1, -5 and -9 in the spinal cord after SCI. However, they did not observe the presence of ADAMTS-9 in neurons after SCI [34].

Table 2 Deregulated expression of ADAMTS proteoglycanases after central nervous system injuries

To summarize, CNS injuries including ischemic stroke or SCI lead to the upregulation of different combinations of ADAMTS proteoglycanases, respectively ADAMTS-1, -4, -9 and ADAMTS-1, -5, -9 (Table 2). A cytokine regulation and/or cell-specific expression of ADAMTS proteoglycanases expression strongly suggest that each of them may be associated to a specific local turnover of CSPGs, assuming that they have non-redundant and cooperative functions in the CNS. Several clues indicate that ADAMTS proteoglycanases may have both beneficial and deleterious effects after CNS injuries as described hereafter and summarized in Figure 1.

Figure 1

Roles of ADAMTS proteoglycanases in the physiological and pathological central nervous system. Schematic representation of described (filled lines)/hypothetical (dotted lines) roles of ADAMTS proteoglycanases in the physiological (green) and pathological (red) CNS, with corresponding major references listed below. This schema also illustrates that ADAMTS proteoglycanases can achieve several functions in the physiological and pathological CNS via the cleavage of their substrates, so far CSPGs or Reelin, but also independently of their proteolytic activity. ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; CNS, central nervous system; CSPGs, chondroitin sulfate proteoglycans.

ADAMTS proteoglycanases: inflammatory and anti-angiogenic proteases in the central nervous system?

ADAMTS proteoglycanases and macrophage infiltration

A growing body of evidence suggests that ADAMTS proteoglycanases may be involved in the neuroinflammatory response after CNS injury by promoting the infiltration of macrophages into the CNS:

  1. 1.

    ADAMTS-4 is increased during the differentiation of human monocytes into macrophages in vitro[37] and is required for macrophages invasion in vitro[38].

  2. 2.

    Versican is the primary CSPG present in the vasculature and is a potent substrate for ADAMTS proteoglycanases [39], which begs the question of whether upregulation of the ADAMTS proteoglycanases at the neurovascular unit may participate in the leakage of the blood brain/spinal cord barrier after ischemic stroke or SCI. It would be consistent with local degradation of versican by ADAMTS proteoglycanases synthesized by endothelial cells [4042] and/or monocytes/macrophages [36].

Altogether, it can be hypothesized that ADAMTS proteoglycanases, particularly ADAMTS-4, may be a key player of the macrophage infiltration into the CNS after injury either directly or indirectly by promoting the leakage of the blood brain/spinal cord barrier.

ADAMTS proteoglycanases and angiogenesis

The involvement of ADAMTS proteases has been largely investigated in angiogenesis mechanisms occurring in cancer, yet similar mechanisms may also occur in the CNS. Both proteinase-dependent and independent anti-angiogenic functions for most of the ADAMTS proteases, including proteoglycanases, have been described [4245]. For instance, it has been proposed that ADAMTS proteoglycanases can negatively regulate angiogenesis via the sequestration of the most potent pro-angiogenic factor, VEGF (vascular endothelial growth factor) or via the release of anti-angiogenic fragments derived from thrombospondin type 1 and 2 motifs. Besides its pro-angiogenic effect, VEGF has also been shown to promote vascular permeability, neuroinflammation, neuritic growth and neuroprotection particularly after ischemic stroke or SCI [46]. Therefore, it is possible to hypothesize that the sequestration of VEGF by endogenous ADAMTS proteoglycanases may have both protective and harmful effects in the CNS. To conclude, the effect of ADAMTS proteoglycanases in angiogenesis processes after acute CNS injuries remains largely unknown and deserves further investigation.

ADAMTS proteoglycanases and neurorepair

Neurorepair including neuroregeneration and remyelination is compromised in the chronic phase of stroke or SCI partly because of an overexpression of CSPGs [47, 48]. In parallel with the upregulation of CSPGs within the glial scar, ischemic stroke is also associated with degradation of PNNs containing CSPGs at the lesion site, but also in the peri-ischemic area and the contralateral hemisphere after permanent MCAO. Although the degradation of the PNNs occurred predominantly in the lesion core and was associated with the invasion of monocytes/macrophages, the transient reduction of neurons containing PNNs in the peri-ischemic area or the contralateral hemisphere is more likely associated with an attempt at neurorepair [49]. It is tempting to hypothesize that after CNS injuries, the loss of PNNs may be caused by increased local secretion of neuronal ADAMTS proteoglycanases (as described for ADAMTS-1 and ADAMTS-9) triggering adverse effects: neuroinflammation in the lesion core and an attempt at neuroplasticity in surrounding tissues. However, these attempts at axonal regeneration/collateral sprouting are too transient and/or unsuccessful to efficiently penetrate the repellant CSPGs-rich glial scar and to improve long term functional recovery.

The inhibition of CSPGs can be relieved by the bacterial enzyme chondroitinase ABC which removes the chondroitin sulfate chains from the core proteins, thus promoting axonal regeneration/collateral sprouting of a wide variety of neuron tracts and functional recovery after stroke or SCI [4957]. However, the core proteins remain intact and can still inhibit neuroregeneration/remyelination. ADAMTS proteoglycanases are physiological enzymes capable of achieving the complete degradation of CSPGs [1, 2]. Surprisingly, evidence that ADAMTS proteoglycanases may improve neurite growth and axonal regeneration/collateral sprouting has recently emerged:

  1. 1.

    Hamel and collaborators (2008) reported that a recombinant active ADAMTS-4 can promote neurite growth of cortical neurons in vitro dependently or independently of its proteolytic activity as described above [26].

  2. 2.

    Cua and collaborators (2013) reported that ADAMTS-4 was more efficient at degrading CSPGs and inducing subsequent neurite growth in vitro than chondroitinase ABC or MMPs [58].

  3. 3.

    The treatment of mice submitted to contusion-induced SCI with recombinant ADAMTS-4 improves axonal regeneration/collateral sprouting of serotoninergic fibers and subsequent functional recovery via the degradation of neurocan [24].

In addition to the inhibition of axonal regeneration/collateral sprouting in CNS injuries, CSPGs are also strongly upregulated within the white matter where they contribute to the inhibition of remyelination of injured axons. Interestingly, chondroitinase ABC can prevent CSPGs-inhibition of remyelination in vitro and in vivo after contusion-induced SCI in rats and in a lysolecithin-induced demyelination model in mice [47, 48, 59]. Moreover, olfactory ensheathing cell-based therapies promote remyelination after acute injuries [60] and these cells were recently reported to express ADAMTS-4 [61, 62]. This raises the question of whether ADAMTS-4 or any ADAMTS proteoglycanases could improve remyelination of injured axons more efficiently than chondroitinase ABC does.

To conclude, the overexpression of ADAMTS proteoglycanases induced by acute CNS injuries such as stroke or SCI seems harmful in the acute phase through enhancing neuroinflammation, and beneficial (or at least safe) in later phases to initiate neurorepair (Figure 1). A combination approach may represent an attractive therapeutic opportunity: first, the administration of an inhibitor of ADAMTS proteoglycanases activity, such as TIMP-3 (tissue inhibitor of metalloproteinases-3) [63], or an inhibitor of their synthesis, such as the anti-inflammatory compound WIN-34B [29], in the acute phase of CNS injuries to overcome ADAMTS-induced macrophage infiltration; then, the administration of active ADAMTS proteoglycanases in the chronic phase of CNS injuries to enhance neuroregeneration/neuroplasticity/remyelination, by using already commercially available recombinant proteins, or by using lentiviral gene therapy approach in cell transplantation-based therapies. However, the administration of any therapeutic molecule to treat CNS disorders is challenging; in addition to finding the most appropriate timing, their passage across the blood brain/spinal cord barrier can also be problematic [64]. However, nasal delivery of therapeutic molecules to the brain allows them to bypass the barrier and represents a safe and convenient system for pre-clinical and clinical studies [65].


Exciting evidence for the involvement of ADAMTS proteoglycanases in the CNS in mechanisms governing synaptic plasticity during development and aging has been proposed quite recently and has emphasized the proteolytic-dependent and -independent actions of these ADAMTS proteoglycanases. However, more research is required to determine whether ADAMTS proteoglycanases have redundant spatiotemporal expressions and functions in the physiological and also pathological CNS. After CNS injuries such as stroke and SCI, it seems obvious that ADAMTS proteoglycanases may be detrimental in the acute phase of injury while they may have a beneficial role later on as summarized in Figure 1. Even though their roles in angiogenesis and macrophage infiltration within the injured CNS have not been addressed yet, the early inhibition of ADAMTS proteoglycanases synthesis/activity after brain or spinal cord injuries may represent a rational therapeutic approach to limit the invasion of macrophages and/or to promote angiogenesis. This review clearly supports the postulate that the ADAMTS proteoglycanases, in particular ADAMTS-4, should be considered as key proteases to promote neurorepair after CNS injuries.



A disintegrin and metalloproteinase with thrombospondin motifs


Central nervous system


Chondroitin sulfate proteoglycan


Extracellular matrix


Extracellular signal-regulated kinase






Mitogen activated protein


Mitogen activated protein kinase


Matrix metalloproteinase


Nuclear factor kappa-light-chain-enhancer of activated B cells


Perineuronal net


Postsynaptic density protein 95


Spinal cord injury


Synaptosomal-associated protein 25


Transforming growth factor-β


Tissue inhibitor of metalloproteinases-3


Transient middle cerebral artery occlusion


Tumor necrosis factor-α


Vascular endothelial growth factor.


  1. 1.

    Tang BL: ADAMTS: a novel family of extracellular matrix proteases. Int J Biochem Cell Biol 2001, 33:33–44.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Apte SS: A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family. Int J Biochem Cell Biol 2004, 36:981–985.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Flannery CR, Zeng W, Corcoran C, Collins-Racie LA, Chockalingam PS, Hebert T, Mackie SA, McDonagh T, Crawford TK, Tomkinson KN, LaVallie ER, Morris EA: Autocatalytic cleavage of ADAMTS-4 (Aggrecanase-1) reveals multiple glycosaminoglycan-binding sites. J Biol Chem 2002, 277:42775–42780.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Lin EA, Liu CJ: The role of ADAMTSs in arthritis. Protein Cell 2010, 1:33–47.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Wang P, Tortorella M, England K, Malfait AM, Thomas G, Arner EC, Pei D: Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network. J Biol Chem 2004, 279:15434–15440.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Tortorella M, Pratta M, Liu RQ, Abbaszade I, Ross H, Burn T, Arner E: The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage. J Biol Chem 2000, 275:25791–25797.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Rodriguez-Manzaneque JC, Milchanowski AB, Dufour EK, Leduc R, Iruela-Arispe ML: Characterization of METH-1/ADAMTS1 processing reveals two distinct active forms. J Biol Chem 2000, 275:33471–33479.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Gao G, Westling J, Thompson VP, Howell TD, Gottschall PE, Sandy JD: Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. J Biol Chem 2002, 277:11034–11041.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Majerus EM, Zheng X, Tuley EA, Sadler JE: Cleavage of the ADAMTS13 propeptide is not required for protease activity. J Biol Chem 2003, 278:46643–46648.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Gao G, Plaas A, Thompson VP, Jin S, Zuo F, Sandy JD: ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. J Biol Chem 2004, 279:10042–10051.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Porter S, Clark IM, Kevorkian L, Edwards DR: The ADAMTS metalloproteinases. Biochem J 2005, 386:15–27.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Llamazares M, Cal S, Quesada V, López-Otín C: Identification and characterization of ADAMTS-20 defines a novel subfamily of metalloproteinases-disintegrins with multiple thrombospondin-1 repeats and a unique GON domain. J Biol Chem 2003, 278:13382–13389.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Nicholson AC, Malik SB, Logsdon JM, Van Meir EG: Functional evolution of ADAMTS genes: evidence from analyses of phylogeny and gene organization. BMC Evol Biol 2005, 5:11.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Stanton H, Melrose J, Little CB, Fosang AJ: Proteoglycan degradation by the ADAMTS family of proteinases. Biochim Biophys Acta 2011, 1812:1616–1629.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Rolls A, Shechter R, Schwartz M: The bright side of the glial scar in CNS repair. Nat Rev Neurosci 2009, 10:235–241.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Yuan W, Matthews RT, Sandy JD, Gottschall PE: Association between protease-specific proteolytic cleavage of brevican and synaptic loss in the dentate gyrus of kainate-treated rats. Neuroscience 2002, 114:1091–1101.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Miguel RF, Pollak A, Lubec G: Metalloproteinase ADAMTS-1 but not ADAMTS-5 is manifold overexpressed in neurodegenerative disorders as Down syndrome, Alzheimer’s and Pick’s disease. Brain Res Mol Brain Res 2005, 133:1–5.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Jungers KA, Le Goff C, Somerville RP, Apte SS: Adamts9 is widely expressed during mouse embryo development. Gene Expr Patterns 2005, 5:609–617.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Howell MD, Torres-Collado AX, Iruela-Arispe ML, Gottschall PE: Selective decline of synaptic protein levels in the frontal cortex of female mice deficient in the extracellular metalloproteinase ADAMTS1. PLoS One 2012, 7:e47226.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Krstic D, Rodriguez M, Knuesel I: Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. PLoS One 2012, 7:e47793.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Cross AK, Haddock G, Surr J, Plumb J, Bunning RA, Buttle DJ, Woodroofe MN: Differential expression of ADAMTS-1, -4, -5 and TIMP-3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis. J Autoimmun 2006, 26:16–23.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Haddock G, Cross AK, Plumb J, Surr J, Buttle DJ, Bunning RA, Woodroofe MN: Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter. Mult Scler 2006, 12:386–396.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Cross AK, Haddock G, Stock CJ, Allan S, Surr J, Bunning RA, Buttle DJ, Woodroofe MN: ADAMTS-1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes. Brain Res 2006, 1088:19–30.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Tauchi R, Imagama S, Natori T, Ohgomori T, Muramoto A, Shinjo R, Matsuyama Y, Ishiguro N, Kadomatsu K: The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury. J Neuroinflammation 2012, 9:53.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Hamel MG, Mayer J, Gottschall PE: Altered production and proteolytic processing of brevican by transforming growth factor beta in cultured astrocytes. J Neurochem 2005, 93:1533–1541.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Hamel MG, Ajmo JM, Leonardo CC, Zuo F, Sandy JD, Gottschall PE: Multimodal signaling by the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) promotes neurite extension. Exp Neurol 2008, 210:428–440.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Bonneh-Barkay D, Wiley CA: Brain extracellular matrix in neurodegeneration. Brain Pathol 2009, 19:573–585.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM, Risbud MV: Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol 2013, 182:2310–2321.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Huh JE, Seo BK, Park YC, Kim JI, Lee JD, Choi DY, Baek YH, Park DS: WIN-34B, a new herbal medicine, inhibits the inflammatory response by inactivating IκB-α phosphorylation and mitogen activated protein kinase pathways in fibroblast-like synoviocytes. J Ethnopharmacol 2012, 143:779–786.

    Article  PubMed  Google Scholar 

  30. 30.

    Mimata Y, Kamataki A, Oikawa S, Murakami K, Uzuki M, Shimamura T, Sawai T: Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Int J Rheum Dis 2012, 15:36–44.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Séguin CA, Bojarski M, Pilliar RM, Roughley PJ, Kandel RA: Differential regulation of matrix degrading enzymes in a TNFalpha-induced model of nucleus pulposus tissue degeneration. Matrix Biol 2006, 25:409–418.

    Article  PubMed  Google Scholar 

  32. 32.

    Reid MJ, Cross AK, Haddock G, Allan SM, Stock CJ, Woodroofe MN, Buttle DJ, Bunning RA: ADAMTS-9 expression is up-regulated following transient middle cerebral artery occlusion (tMCAo) in the rat. Neurosci Lett 2009, 452:252–257.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA: Genomic analysis of reactive astrogliosis. J Neurosci 2012, 32:6391–6410.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Demircan K, Yonezawa T, Takigawa T, Topcu V, Erdogan S, Ucar F, Armutcu F, Yigitoglu MR, Ninomiya Y, Hirohata S: ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse. Neurosci Lett 2013, 544:25–30.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Sasaki M, Seo-Kiryu S, Kato R, Kita S, Kiyama H: A disintegrin and metalloprotease with thrombospondin type1 motifs (ADAMTS-1) and IL-1 receptor type 1 mRNAs are simultaneously induced in nerve injured motor neurons. Brain Res Mol Brain Res 2001, 89:158–163.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Ashlin TG, Kwan AP, Ramji DP: Regulation of ADAMTS-1, -4 and -5 expression in human macrophages: differential regulation by key cytokines implicated in atherosclerosis and novel synergism between TL1A and IL-17. Cytokine 2013, 64:234–242.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Wågsäter D, Björk H, Zhu C, Björkegren J, Valen G, Hamsten A, Eriksson P: ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis 2008, 196:514–522.

    Article  PubMed  Google Scholar 

  38. 38.

    Ren P, Zhang L, Xu G, Palmero LC, Albini PT, Coselli JS, Shen YH, LeMaire SA: ADAMTS-1 and ADAMTS-4 levels are elevated in thoracic aortic aneurysms and dissections. Ann Thorac Surg 2013, 95:570–577.

    Article  PubMed  Google Scholar 

  39. 39.

    Westling J, Gottschall PE, Thompson VP, Cockburn A, Perides G, Zimmermann DR, Sandy JD: ADAMTS4 (aggrecanase-1) cleaves human brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein. Biochem J 2004, 377:787–795.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Didangelos A, Mayr U, Monaco C, Mayr M: Novel role of ADAMTS-5 protein in proteoglycan turnover and lipoprotein retention in atherosclerosis. J Biol Chem 2012, 287:19341–19345.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Diamantis I, Lüthi M, Hösli M, Reichen J: Cloning of the rat ADAMTS-1 gene and its down regulation in endothelial cells in cirrhotic rats. Liver 2000, 20:165–172.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Hsu YP, Staton CA, Cross N, Buttle DJ: Anti-angiogenic properties of ADAMTS-4 in vitro. Int J Exp Pathol 2012, 93:70–77.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Basile DP, Fredrich K, Chelladurai B, Leonard EC, Parrish AR: Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. Am J Physiol Renal Physiol 2008, 294:F928-F936.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Lo PH, Lung HL, Cheung AK, Apte SS, Chan KW, Kwong FM, Ko JM, Cheng Y, Law S, Srivastava G, Zabarovsky ER, Tsao SW, Tang JC, Stanbridge EJ, Lung ML: Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis. Cancer Res 2010, 70:5567–5576.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kumar S, Sharghi-Namini S, Rao N, Ge R: ADAMTS5 functions as an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity. Am J Pathol 2012, 181:1056–1068.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Lafuente JV, Ortuzar N, Bengoetxea H, Bulnes S, Argandoña EG: Vascular endothelial growth factor and other angioglioneurins: key molecules in brain development and restoration. Int Rev Neurobiol 2012, 102:317–346.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Döring A, Sloka S, Stirling DP, Rivest S, Yong VW: Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol 2012, 72:419–432.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Siebert JR, Stelzner DJ, Osterhout DJ: Chondroitinase treatment following spinal contusion injury increases migration of oligodendrocyte progenitor cells. Exp Neurol 2011, 231:19–29.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Hobohm C, Günther A, Grosche J, Rossner S, Schneider D, Brückner G: Decomposition and long-lasting downregulation of extracellular matrix in perineuronal nets induced by focal cerebral ischemia in rats. J Neurosci Res 2005, 80:539–548.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Gherardini L, Gennaro M, Pizzorusso T: Perilesional treatment with chondroitinase ABC and motor training promote functional recovery after stroke in rats. Cereb Cortex 2013. epub ahead of print

    Google Scholar 

  51. 51.

    Hill JJ, Jin K, Mao XO, Xie L, Greenberg DA: Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats. Proc Natl Acad Sci U S A 2012, 109:9155–9160.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Soleman S, Yip PK, Duricki DA, Moon LD: Delayed treatment with chondroitinase ABC promotes sensorimotor recovery and plasticity after stroke in aged rats. Brain 2012, 135:1210–1223.

    Article  PubMed  Google Scholar 

  53. 53.

    Zuo J, Neubauer D, Dyess K, Ferguson TA, Muir D: Degradation of chondroitin sulfate proteoglycan enhances the neurite-promoting potential of spinal cord tissue. Exp Neurol 1998, 154:654–662.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Zuo J, Neubauer D, Graham J, Krekoski CA, Ferguson TA, Muir D: Regeneration of axons after nerve transection repair is enhanced by degradation of chondroitin sulfate proteoglycan. Exp Neurol 2002, 176:221–228.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Bradbury EJ, Carter LM: Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull 2011, 84:306–316.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB: Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002, 416:636–640.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Tom VJ, Sandrow-Feinberg HR, Miller K, Santi L, Connors T, Lemay MA, Houlé JD: Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord. J Neurosci 2009, 29:14881–14890.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Cua RC, Lau LW, Keough MB, Midha R, Apte SS, Yong VW: Overcoming neurite-inhibitory chondroitin sulfate proteoglycans in the astrocyte matrix. Glia 2013, 61:972–984.

    Article  PubMed  Google Scholar 

  59. 59.

    Siebert JR, Osterhout DJ: The inhibitory effects of chondroitin sulfate proteoglycans on oligodendrocytes. J Neurochem 2011, 119:176–188.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Sasaki M, Lankford KL, Radtke C, Honmou O, Kocsis JD: Remyelination after olfactory ensheathing cell transplantation into diverse demyelinating environments. Exp Neurol 2011, 229:88–98.

    Article  PubMed  Google Scholar 

  61. 61.

    Mayeur A, Duclos C, Honoré A, Gauberti M, Drouot L, Do Rego JC, Bon-Mardion N, Jean L, Vérin E, Emery E, et al.: Potential of olfactory ensheathing cells from different sources for spinal cord repair. PLoS One 2013, 8:e62860.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Guérout N, Derambure C, Drouot L, Bon-Mardion N, Duclos C, Boyer O, Marie JP: Comparative gene expression profiling of olfactory ensheathing cells from olfactory bulb and olfactory mucosa. Glia 2010, 58:1570–1580.

    PubMed  Google Scholar 

  63. 63.

    Lim NH, Kashiwagi M, Visse R, Jones J, Enghild JJ, Brew K, Nagase H: Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications. Biochem J 2010, 431:113–122.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Daneman R: The blood–brain barrier in health and disease. Ann Neurol 2012, 72:648–672.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Pardeshi CV, Belgamwar VS: Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood–brain barrier: an excellent platform for brain targeting. Expert Opin Drug Deliv 2013, 10:957–972.

    CAS  Article  PubMed  Google Scholar 

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This work was supported by the University of Eastern Finland and the ERANET-Neuron research program ‘ProteA: Proteases before, during and after stroke’, 2012–2015.

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Correspondence to Sighild Lemarchant.

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Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SL planned and wrote the review. All authors gave critical comments on the draft of the manuscript based on their expertise on pre-clinical (SL, MP, DV, KK, JK) and/or clinical studies (JM, EE) on stroke and/or spinal cord injuries. SL and MP prepared the tables/figures. KK helped in editing the manuscript. All authors read and approved the final version of the manuscript.

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Lemarchant, S., Pruvost, M., Montaner, J. et al. ADAMTS proteoglycanases in the physiological and pathological central nervous system. J Neuroinflammation 10, 899 (2013).

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  • A disintegrin and metalloproteinase with thrombospondin motifs
  • Proteoglycanases
  • Stroke
  • Spinal cord injury
  • Chondroitin sulfate proteoglycan
  • Synaptic plasticity
  • Inflammation
  • Angiogenesis
  • Neurorepair