MMP-2 and MMP-9 are elevated in spinal cord and skin in a mouse model of ALS.
We aimed to clarify the role of matrix metalloproteinases (MMP) as a possible link between neurodegeneration and skin pathology in ALS by determination of gelatinase MMP-2 and MMP-9 in spinal cord and skin of transgenic SOD1((G93A)) mice. To elucidate mechanisms influencing MMPs, markers of oxidative damage (malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and 8-hydroxy-2'-deoxyguanosine (8OH2'dG)) as well as cytokines (tumor necrosis factor alpha (TNF-alpha) and interleukin 1ss (IL-1ss)) were determined. We measured MMP-9, MMP-2, 3-NT, TNF-alpha, and IL-1ss using ELISA, MDA using High Performance Liquid Chromatography (HPLC) and 8OH2'dG using HPLC with electrochemical detection (HPLC-ECD) in SOD1 and WT. MMP-9 was elevated in spinal cord and skin of SOD1 at 90 days (p=0.009, p<0.001) and 120 days (p<0.01, p=0.04). MMP-2 was elevated in the spinal cord at 90 days (p=0.01) and in the skin at 120 days (p=0.039). We observed a correlation of MMP-9 in spinal cord and skin of SOD1 (p=0.04). MDA was elevated in the spinal cord of SOD1 at 90 and 120 days (p=0.00006, p=0.01) and 8OH2'dG at 90 days (p=0.048). IL-1ss was elevated in the spinal cord of SOD1 at 120 days (p=0.02). Our data confirms that gelatinase MMPs are a common factor linking neurodegeneration and skin changes in ALS. It suggests that oxidative stress and microglial-derived cytokines contribute to the elevation of gelatinase MMPs especially in later stages of disease. Our data raises the question whether the skin may function as a biomarker for specific aspects of disease pathology in ALS.
Fang
Lubin
L
Department of Neurology, University of Ulm, 89081 Ulm, Germany.
Teuchert
Marko
M
Huber-Abel
Friederike
F
Schattauer
Dagmar
D
Hendrich
Corinna
C
Dorst
Johannes
J
Zettlmeissel
Heinz
H
Wlaschek
Meinhard
M
Scharffetter-Kochanek
Karin
K
Kapfer
Tamara
T
Tumani
Hayrettin
H
Ludolph
Albert C
AC
Brettschneider
Johannes
J
D000375:Aging / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D018384:Oxidative Stress / Q000502:physiology; D012867:Skin / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D053583:Interleukin-1beta; C000606290:SOD1 protein, human; D014409:Tumor Necrosis Factor-alpha; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse