Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro

Selvaraju, Raghuram; Bernasconi, Lilia; Losberger, Christophe; Graber, Pierre; Kadi, Linda; Avellana‐Adalid, Virginia; Picard-Riéra, Nathalie; Evercooren, Anne Baron-Van; Cirillo, R; Kosco‐Vilbois, Marie H.; Feger, Georg; Papoian, Ruben; Boschert, Ursula

doi:10.1016/j.mcn.2003.12.014

Cited by 134 publications

(122 citation statements)

References 89 publications

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“…Note that analysis of uninjured spinal cords indicated that KO mice had less white matter than WT. This is consistent with previous in vitro and in vivo studies indicating that OPN Ϫ/Ϫ mice contained significantly less MBP than WT mice and that OPN expression is upregulated during demyelination and remyelination (Selvaraju et al, 2004). OPN therefore may play a role in remyelination after spinal cord injury.…”

Section: Locomotor Recovery and Histologysupporting

confidence: 92%

Osteopontin-Deficient Mice Exhibit Less Inflammation, Greater Tissue Damage, and Impaired Locomotor Recovery from Spinal Cord Injury Compared with Wild-Type Controls

Hashimoto¹,

Sun

Rittling

et al. 2007

J. Neurosci.

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Osteopontin (OPN) is expressed in many tissues during inflammatory responses. After spinal cord injury, microglia expresses OPN at the site of injury during the early to subacute stages. However, the function of OPN in spinal cord injury is not well understood. This study examines the responses of OPN knock-out (KO) and wild-type (WT) mice to spinal cord contusion injury. KO and WT mice were injured with a modified New York University impactor. Weights of 10 or 5.6 g were dropped 6.25 mm onto the T13 spinal cord under isoflurane anesthesia. At 24 h, homogenized spinal cords were analyzed for total potassium concentration to estimate lesion volumes. Expression of apoptotic genes, proinflammatory cytokines, and nerve growth factors was measured by reverse transcription (RT)-PCR and Western blot. In a series of animals, locomotor recovery was assessed with the Basso mouse scale (BMS) for 6 weeks, and histological analyses was performed to determine tissue preservation. Lesion volume showed no significant differences between KO and WT mice at 24 h. RT-PCR indicated that KO mice had significantly less Bcl-2, tumor necrosis factor-␣, interleukin-1␤, and interleukin-6 mRNA compared with WT controls. Western blot also showed that KO had significantly less Bcl-2 7 d after spinal cord injury. KO mice had significantly worse BMS locomotor scores than WT at 6 weeks. KO mice also had a significantly reduced area of spared white matter and fewer neuronal-specific nuclear protein-positive neurons in the spinal cord surrounding the impact site. This result supports a potential neuroprotective role for OPN in the inflammatory response to spinal cord injury.

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Section: Locomotor Recovery and Histologysupporting

confidence: 92%

Osteopontin-Deficient Mice Exhibit Less Inflammation, Greater Tissue Damage, and Impaired Locomotor Recovery from Spinal Cord Injury Compared with Wild-Type Controls

Hashimoto¹,

Sun

Rittling

et al. 2007

J. Neurosci.

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“…We found upregulation of Pdgfa, Pdgfb, Vegfa, Vegfb, Tgfb1, Igf1, and Spp1, all of which have been reported to promote oligodendrocyte differentiation (Baumann and Pham-Dinh, 2001;Bradl and Lassmann, 2010;Chesik et al, 2008;Diemel et al, 2003;Frost et al, 2003;Hinks and Franklin, 1999;Hsieh et al, 2004;Kim et al, 2009;Selvaraju et al, 2004;Vela et al, 2002;Woodruff et al, 2004). Interestingly, we did not find upregulation of Gdnf or Fgf2, as reported by Gudi et al (2011).…”

Section: Discussionsupporting

confidence: 63%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

307

268

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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“…In particular, we are alerted to a study that shows that recombinant OPN stimulates the synthesis of myelin basic protein and promotes myelin sheath formation in mixed cortical cultures from embryonic mouse brain. 52 The authors suggest that OPN may act as a novel regulator of myelination and remyelination. If so, then antagonizing the effect of OPN may ameliorate neuroinflammation but could have adverse effects on repair of myelin.…”

Section: Discussionmentioning

confidence: 99%

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

DaSilva

Liaw

Yong

2010

The American Journal of Pathology

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A role for osteopontin (OPN) in promoting disease activity of multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) has recently been suggested. As the biological activity of OPN is heavily influenced by posttranslational processing, we investigated the capacity of matrix metalloproteinase (MMP)-12 to cleave OPN and determined whether this influenced disease activity. We found that OPN mRNA and protein expression in the spinal cord increased with EAE disease in C57BL/6 mice concurrently with MMP-12 expression. A Western blot of EAE and control spinal cords revealed different OPNimmunoreactive bands, with a pattern that was similar to MMP-12 cleavage of recombinant OPN in vitro. In addition, OPN fragments in the spinal cord of EAEafflicted mice were reduced in MMP-12 ؊/؊ mice compared with wild-type controls. However, examination of OPN ؊/؊ mice in short-and long-term experiments revealed no difference in EAE outcomes from wildtype animals. OPN/MMP-12 double null mice were generated, and it was revealed that MMP-12 ؊/؊ mice had a worsening of disease compared with wild-type mice, which returned to wild-type levels in the OPN/ MMP-12 double null mice. These results suggest that EAE disease activity may be modulated by the cleavage of OPN by

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Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro

Cited by 134 publications

References 89 publications

Osteopontin-Deficient Mice Exhibit Less Inflammation, Greater Tissue Damage, and Impaired Locomotor Recovery from Spinal Cord Injury Compared with Wild-Type Controls

Osteopontin-Deficient Mice Exhibit Less Inflammation, Greater Tissue Damage, and Impaired Locomotor Recovery from Spinal Cord Injury Compared with Wild-Type Controls

Identification of a microglia phenotype supportive of remyelination

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

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