Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9.
Differential vulnerability among motor neuron (MN) subtypes is a fundamental feature of amyotrophic lateral sclerosis (ALS): fast-fatigable (FF) MNs are more vulnerable than fast fatigue-resistant (FR) or slow (S) MNs. The reason for this selective vulnerability remains enigmatic. We report here that the extracellular matrix (ECM) protein osteopontin (OPN) is selectively expressed by FR and S MNs and ALS-resistant motor pools, whereas matrix metalloproteinase-9 (MMP-9) is selectively expressed by FF MNs. OPN is secreted and accumulated as extracellular granules in ECM in three ALS mouse models and a human ALS patient. In SOD1(G93A) mice, OPN/MMP-9 double positivity marks remodeled FR and S MNs destined to compensate for lost FF MNs before ultimately dying. Genetic ablation of OPN in SOD1(G93A) mice delayed disease onset but then accelerated disease progression. OPN induced MMP-9 up-regulation via αvβ3 integrin in ChAT-expressing Neuro2a cells, and also induced CD44-mediated astrocyte migration and microglial phagocytosis in a non-cell-autonomous manner. Our results demonstrate that OPN expressed by FR/S MNs is involved in the second-wave neurodegeneration by up-regulating MMP-9 through αvβ3 integrin in the mouse model of ALS. The differences in OPN/MMP-9 expression profiles in MN subsets partially explain the selective MN vulnerability in ALS.
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Yuta
Y
Morisaki
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Mamiko
M
Niikura
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Mizuho
M
Watanabe
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Kosuke
K
Onishi
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Shogo
S
Tanabe
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Yasuhiro
Y
Moriwaki
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Takashi
T
Okuda
Department of Neurology, Matsumoto Medical Center, Chushin-Matsumoto Hospital, Matsumoto 399-0021, Japan.
Shinji
S
Ohara
Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Shigeo
S
Murayama
Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Masaki
M
Takao
Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Sae
S
Uchida
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
Koji
K
Yamanaka
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Hidemi
H
Misawa
D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009046:Motor Neurons / Q000502:physiology*; D053495:Osteopontin / Q000378:metabolism*
D039302:Integrin alphaVbeta3; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; D053495:Osteopontin; D020780:Matrix Metalloproteinase 9