ADAMTS4 Gene

title: ADAMTS4 Gene

ADAMTS4 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 4)

<div class="infobox infobox-gene"> [@lemarchant2016]

| Property | Value | [@lemarchant2013]
|----------|-------| [@rodrigues2019]
| Gene Symbol | ADAMTS4 | [@bhagavathi2023]
| Full Name | ADAM Metallopeptidase with Thrombospondin Type 1 Motif 4 | [@hamel2008]
| Aliases | Aggrecanase-1, ADMP-1 |
| Chromosomal Location | 1q23.3 |
| NCBI Gene ID | [9507](https://www.ncbi.nlm.nih.gov/gene/9507) |
| OMIM ID | [603282](https://omim.org/entry/603282) |
| Ensembl ID | [ENSG00000158859](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158859) |
| UniProt ID | [O75173](https://www.uniprot.org/uniprot/O75173) |
| Encoded Protein | [ADAMTS-4 protein](/proteins/adamts4-protein) |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), osteoarthritis, spinal cord injury |

</div>

Overview

title: ADAMTS4 Gene

ADAMTS4 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 4)

<div class="infobox infobox-gene"> [@lemarchant2016]

| Property | Value | [@lemarchant2013]
|----------|-------| [@rodrigues2019]
| Gene Symbol | ADAMTS4 | [@bhagavathi2023]
| Full Name | ADAM Metallopeptidase with Thrombospondin Type 1 Motif 4 | [@hamel2008]
| Aliases | Aggrecanase-1, ADMP-1 |
| Chromosomal Location | 1q23.3 |
| NCBI Gene ID | [9507](https://www.ncbi.nlm.nih.gov/gene/9507) |
| OMIM ID | [603282](https://omim.org/entry/603282) |
| Ensembl ID | [ENSG00000158859](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158859) |
| UniProt ID | [O75173](https://www.uniprot.org/uniprot/O75173) |
| Encoded Protein | [ADAMTS-4 protein](/proteins/adamts4-protein) |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), osteoarthritis, spinal cord injury |

</div>

Overview

ADAMTS4 is a human gene whose product aDAMTS4** encodes a member of the ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin motifs) family of secreted zinc metalloproteinases. ADAMTS-4, also known as aggrecanase-1, is a multidomain extracellular protease with broad substrate specificity that plays important roles in both the peripheral and central nervous system. Variants in ADAMTS4 have been implicated in Alzheimer's Disease (AD), Osteoarthritis, Spinal Cord Injury and CNS Repair. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Function

ADAMTS4 encodes a member of the ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin motifs) family of secreted zinc metalloproteinases. ADAMTS-4, also known as aggrecanase-1, is a multidomain extracellular protease with broad substrate specificity that plays important roles in both the peripheral and central nervous system.

Key normal physiological functions include:

• Extracellular matrix (ECM) remodeling — ADAMTS-4 cleaves aggrecan and other proteoglycans (versican, brevican, neurocan) in the ECM, facilitating tissue remodeling during development and repair
• Perineuronal net (PNN) degradation — Cleaves brevican and other chondroitin sulfate proteoglycans (CSPGs) that form PNNs, structures critical for synaptic stability and [neural plasticity](/mechanisms/synaptic-plasticity)
• Amyloid-beta clearance — Identified as an [amyloid-beta (Aβ)](/proteins/amyloid-beta)-degrading enzyme that can cleave Aβ peptides, potentially contributing to amyloid homeostasis in the brain
• Neuroinflammatory modulation — Expression is upregulated in reactive [astrocytes](/cell-types/astrocytes) and [microglia](/cell-types/microglia) during neuroinflammation
• Spinal cord plasticity — Promotes axonal regeneration and plasticity after spinal cord injury by degrading inhibitory CSPGs

Disease Associations

Alzheimer's Disease (AD)

ADAMTS4 has emerged as a significant gene in [Alzheimer's disease](/diseases/alzheimers-disease) through multiple lines of evidence:

• Genome-wide association studies (GWAS) — A missense variant in ADAMTS4 (rs4575098, p.Ile72Val) was identified as a protective factor against AD in a large-scale GWAS meta-analysis of over 94,000 individuals. Carriers of the rare allele showed significantly reduced AD risk (OR ≈ 0.88)
• Amyloid-beta degradation — ADAMTS-4 cleaves Aβ at multiple sites within the peptide, representing a novel Aβ-degrading pathway complementary to [neprilysin](/proteins/neprilysin) and [insulin-degrading enzyme](/entities/insulin-degrading-enzyme)
• Protective variant mechanism — The protective I72V variant increases ADAMTS-4 enzymatic activity, enhancing Aβ clearance and reducing amyloid plaque burden in mouse models
• Perineuronal net disruption — Dysregulated ADAMTS-4 activity in AD may contribute to PNN breakdown, destabilizing synaptic connections and accelerating [tau](/proteins/tau) pathology spread
• Reactive astrocyte expression — ADAMTS4 is highly upregulated in disease-associated [astrocytes](/entities/astrocytes) surrounding amyloid plaques, suggesting a role in the glial response to Aβ deposition

Osteoarthritis

ADAMTS4 plays a well-established role in osteoarthritis through:

• Degradation of aggrecan in articular cartilage, leading to cartilage destruction
• Upregulation by pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)
• Therapeutic target: ADAMTS-4 inhibitors are under investigation for cartilage protection

Spinal Cord Injury and CNS Repair

• ADAMTS-4-mediated degradation of inhibitory CSPGs promotes axonal regeneration after CNS injury
• Therapeutic delivery of ADAMTS-4 enhances functional recovery in spinal cord injury models
• Involved in Wallerian degeneration and nerve remodeling

Expression

ADAMTS4 shows regulated expression across brain regions:

• High expression: Cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus) (particularly CA1 and dentate gyrus), striatum
• Moderate expression: Thalamus, cerebellum, brainstem, spinal cord
• Cellular expression: Primarily [astrocytes](/cell-types/astrocytes), with lower expression in [neurons](/cell-types/neurons) and [oligodendrocytes](/cell-types/oligodendrocytes)
• Disease-state upregulation: Dramatically increased in reactive astrocytes near amyloid plaques in AD brain tissue
• Subcellular localization: Secreted enzyme; localized to the extracellular space and cell surface

• Pro-inflammatory cytokines ([TNF-α](/proteins/tnf-alpha), [IL-1β](/proteins/il1b-protein), [IL-6](/proteins/il6-protein))
• [TGF-β](/proteins/tgfb1-protein) signaling
• Mechanical stress and hypoxia

Gene Structure and Regulation

• Gene size: ~18 kb spanning 8 exons
• Transcript: 4.5 kb mRNA encoding a 837-amino acid preproprotein
• Promoter elements: Contains [NF-κB](/entities/nf-kb), AP-1, and RUNX2 binding sites that mediate inflammatory and mechanical stress responses
• Epigenetic regulation: Promoter methylation modulates expression in disease states

Animal Models

• Adamts4 knockout mice show reduced cartilage degradation in osteoarthritis models but also impaired CSPG turnover in the CNS
• Overexpression models demonstrate enhanced Aβ clearance and reduced plaque burden in [APP](/entities/app-protein) transgenic mice
• Spinal cord injury models show improved axonal regeneration with ADAMTS-4 delivery

Therapeutic Implications

• AD protective variant — The ADAMTS4 I72V variant suggests that enhancing ADAMTS-4 activity could be a therapeutic strategy for AD
• Aβ clearance enhancement — Upregulating ADAMTS-4 expression or activity may complement existing amyloid-targeting therapies
• CSPG degradation for CNS repair — Targeted delivery of ADAMTS-4 to injury sites could promote neural repair
• Dual-edged role — While beneficial for Aβ clearance, excessive ADAMTS-4 activity could disrupt PNNs and worsen synaptic dysfunction

Key Publications

See Also

• [ADAMTS4 Protein](/proteins/adamts4-protein)
• [Alzheimer's disease](/diseases/alzheimers-disease)
• [neural plasticity](/mechanisms/synaptic-plasticity)

External Links

• [NCBI Gene: ADAMTS4](https://www.ncbi.nlm.nih.gov/gene/9507)
• [Ensembl: ENSG00000158859](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158859)
• [UniProt: O75173](https://www.uniprot.org/uniprot/O75173)
• [GeneCards: ADAMTS4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADAMTS4)
• [OMIM: ADAMTS4](https://omim.org/search?search=ADAMTS4)
• [Allen Brain Atlas: ADAMTS4](https://human.brain-map.org/microarray/search/show?search_term=ADAMTS4)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving ADAMTS4 Gene discovered through SciDEX knowledge graph analysis: