ADAMTS4
A disintegrin and metalloproteinase with thrombospondin motifs 4 precursor (EC 3.4.24.82) (ADAM-TS 4) (ADAM-TS4) (ADAMTS-4) (ADMP-1) (Aggrecanase-1) [KIAA0688] [UNQ769/PRO1563]
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Whether disc aging is influenced by factors beyond its local environment is an important unresolved question. Here we performed heterochronic parabiosis in mice to study the effects of circulating factors in young and old blood on age-associated intervertebral disc degeneration. Compared to young isochronic pairs (Y-Y), young mice paired with old mice (Y-O) showed significant increases in levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic tissue degeneration, but negligible changes in cellular senescence markers (p16 , p21 ). Compared to old isochronic pairs (O-O), old mice paired with young mice (O-Y) exhibited a significant decrease in expression of cellular senescence markers (p16, p21, p53), but only marginal decreases in the levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic degeneration. Thus, exposing old mice to young blood circulation greatly suppressed disc cellular senescence, but only slightly decreased disc matrix imbalance and degeneration. Conversely, exposing young mice to old blood accelerated their disc matrix imbalance and tissue degeneration, with little effects on disc cellular senescence. Thus, non-cell autonomous effects of circulating factors on disc cellular senescence and matrix homeostasis are complex and suggest that disc matrix homeostasis is modulated by systemic factors and not solely through local disc cellular senescence.
Keywords
- aging
- heterochronic parabiosis
- intervertebral disc
- proteoglycan
- systemic factors
Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1(-/Δ) mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5× in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments was significantly increased. Additionally, new PG synthesis was reduced 2-3× in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1(-/Δ) mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.
MeSH Terms
- ADAM Proteins
- ADAMTS4 Protein
- Aggrecans
- Aging
- Alkylating Agents
- Animals
- Apoptosis
- Cellular Senescence
- DNA Damage
- DNA Repair
- DNA-Binding Proteins
- Endonucleases
- Gene Expression Regulation, Enzymologic
- Intervertebral Disc
- Intervertebral Disc Degeneration
- Mechlorethamine
- Mice
- Mice, Knockout
- Procollagen N-Endopeptidase
- Radiation, Ionizing
SC1 is a member of the SPARC family of glycoproteins that regulate cell-matrix interactions in the developing brain. SC1 is expressed in astrocytes, but nothing is known about the expression in the aged or after stroke. We found that after focal striatal ischemic infarction in adult rats, SC1 increased in astrocytes surrounding the infarct and in the glial scar, but in aged rats, SC1 was lower at the lesion edge. Glial fibrillary acidic protein (GFAP) also increased, but it was less prominent in reactive astrocytes further from the lesion in the aged rats. On the basis of their differential expression of several molecules, 2 types of reactive astrocytes with differing spatiotemporal distributions were identified. On Days 3 and 7, SC1 was prevalent in cells expressing markers of classic reactive astrocytes (GFAP, vimentin, nestin, S100β), as well as apoliprotein E (ApoE), interleukin 1β, aggrecanase 1 (ADAMTS4), and heat shock protein 25 (Hsp25). Adjacent to the lesion on Days 1 and 3, astrocytes with low GFAP levels and a "starburst" SC1 pattern expressed S100β, ApoE, and Hsp32 but not vimentin, nestin, interleukin 1β, ADAMTS4, or Hsp25. Neither cell type was immunoreactive for NG2,CC-1, CD11b, or ionized calcium-binding adapter-1. Their differing expression of inflammation-related and putatively protective molecules suggests different roles for starburst and classic reactive astrocytes in the early glial responses to ischemia.
MeSH Terms
- ADAM Proteins
- ADAMTS5 Protein
- Adenomatous Polyposis Coli Protein
- Aging
- Animals
- Animals, Newborn
- Apolipoprotein E4
- Astrocytes
- Brain
- CD11b Antigen
- Calcium-Binding Proteins
- Cells, Cultured
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Endothelin-1
- Extracellular Matrix Proteins
- Functional Laterality
- Gene Expression Regulation
- Glial Fibrillary Acidic Protein
- Gliosis
- Heme Oxygenase (Decyclizing)
- Interleukin-1beta
- Male
- Nerve Tissue Proteins
- Rats
- Rats, Sprague-Dawley
- Stroke
- Time Factors
- Vimentin