The Role of Osteopontin in Neurodegenerative Diseases - IOS Press

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Journal of Alzheimer’s Disease 25 (2011) 179–185 DOI 10.3233/JAD-2011-102151 IOS Press

Review

The Role of Osteopontin in Neurodegenerative Diseases Miryam Carecchioa and Cristoforo Comia,b,c,∗ a Department

of Neurology, Amedeo Avogadro University, Novara, Italy Research Centre of Autoimmune Diseases (IRCAD), Amedeo Avogadro University,

b Interdisciplinary

Novara, Italy c Neurorehabilitation

Institute ‘M.L. Novarese’, Moncrivello (VC), Italy

Handling Associate Editor: Daniela Galimberti Accepted 29 January 2011

Abstract. Osteopontin (OPN) was shown to be involved in inflammatory and degenerative processes of the nervous system. In multiple sclerosis, the role of OPN has been studied in the inflammatory phase, where it was shown that the protein levels increase during disease relapses. Moreover, it was shown that subjects who carry a genotype associated with decreased protein levels tend to display a benign course. Taken altogether, these findings suggest that OPN may play a detrimental role in multiple sclerosis, at least in the inflammatory phase. In common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, OPN seems to act as a double-edged sword triggering neuronal toxicity and death in some contexts and functioning as a neuroprotectant in others. The involvement of OPN in several biological pathways and networks calls for more extensive research in order to unravel its role in the different disease phases and its potential as a therapeutic target. Keywords: Alzheimer’s disease, Eta-1, multiple sclerosis, Parkinson’s disease, SPP1

INTRODUCTION Osteopontin (OPN) is a 60 kDa phosphoprotein that is constitutively expressed by several tissues and cells, including the nervous and the immune system. It was initially identified as a bone matrix protein, hence its name. OPN can act both as a matrix protein and as a cytokine, which is released into body fluids [1]. In this context, OPN is also called ETA-1 (early T-cell activation-1) because of its early production upon cell activation [2]. In fact, activated T cells can secrete OPN, enhancing the T-helper 1 (TH1) and inhibiting the T-helper 2 (TH2) responses [3]. More recently it ∗ Correspondence

to: Cristoforo Comi, MD, PhD, Department of Neurology, Amedeo Avogadro University, Via Solaroli 1728100 Novara, Italy. Tel.: +39 0321 3733965; E-mail: comi@med. unipmn.it.

has been shown that OPN is also able to modulate the function of TH17 cells [4], a population of lymphocytes that is crucial in autoimmunity [5]. OPN has been studied in several physiological and pathological conditions where its production is upregulated in response to either inflammation or injury [1]. This concept is well established in the central nervous system (CNS), where OPN expression increases after neuronal damage, exerting the role of glial cell attractant [6]. This review will summarize the state of the art of what is currently known about the role of OPN in neurodegenerative diseases. MULTIPLE SCLEROSIS Multiple sclerosis (MS) is certainly the CNS disease in which the role of OPN has been investigated to

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M. Carecchio and C. Comi / The Role of OPN in Neurodegenerative Diseases

a greater extent. Due to the nature of the disease, which displays a combination of inflammatory and degenerative damage, OPN may exert different functions. In the vast majority of cases (85–90%) MS runs a relapsingremitting course, at least in the first 5–12 years of disease. During this period, tissue damage is believed to rely more on inflammation than cell degeneration. This balance turns in favor of degeneration as the disease progresses into the secondary progressive phase. By contrast, in the minority of patients who have a primary progressive disease course (10–15%), neurodegeneration prevails from the disease onset [7]. In 2001 a seminal work by Chabas and colleagues [8] opened the avenue to explore the function of OPN in MS. The authors first showed that OPN transcript was abundant in plaques dissected from brains of patients with MS, whereas it was absent in control brain tissue; subsequently they confirmed this finding in rat experimental autoimmune encephalomyelitis (EAE) by microarray cDNA analysis of spinal cord tissue. Moreover, they showed that OPN-deficient mice had a milder disease than wild type animals and displayed a single relapse without subsequent exacerbations or progression [8, 9]. Treatment of EAE mice with rOPN has been shown to exacerbate the disease in OPN deficient mice. Indeed, Hur et al. investigated the effect of a daily administration of rOPN during the spontaneous recovery of MOG-induced EAE in OPN deficient mice in order to mimic the condition of patients with MS who display increased plasma levels of OPN before and during clinical relapses [10–12]. Results showed that the ongoing remission of EAE was reversed by treatment with rOPN with induction of a relapse followed by progressive severe disease leading to death. Moreover, these authors showed that rOPN triggered the neurological relapse not only by stimulating expression of pro-inflammatory mediators, such as Th1 and Th17 cytokines in myelin-specific T cells, but also by inhibiting apoptosis of autoreactive immune cells through the regulation of expression of transcription factors (Foxo3 a and NF-kB) and proapoptotic proteins (Bak, Bax, Bim) [12]. These results suggested that OPN might modulate apoptotic elimination of infiltrating lymphocytes and inflammatory cells in CNS lesions and were in line with what Chiocchetti et al. showed, namely that rOPN inhibits activation-induced T cell death in vitro [13]. Another possible role played by OPN in MS may concern its effect in the extracellular matrix of the perivascular cuff [7]. This area surrounds inflamed blood vessels, containing inflammatory lymphocytes,

and is delimited by endothelium on one side and basement membrane on the other side. In fact, OPN is a member of the Sibling (small integrin-binding ligand, N-linked glycoproteins) proteins [14] and is secreted at high levels in the extracellular matrix of the perivascular cuff during EAE induction. At this site OPN may play a role, in synergy with endothelial VCAM-1, in lymphocyte homing to the inflamed brain which is driven by a4␤1 integrin on lymphocytes that can bind both VCAM-1 and OPN. Indeed, antibodies targeting the a4 or ␤1 chains can block human T cell binding to inflamed brain endothelium [15, 16]. Genetic analyses have correlated variations in the Osteopontin (OPN) gene with MS [17–19]. We have previously shown that OPN genotypes may influence MS development and progression due to their influence on OPN levels. Homozygous subjects for haplotype A display lower OPN levels than non-AA subjects. Moreover, AA patients have about 1.5 lower risk of developing MS, a slower switching from a RR to a SP form and milder disease with slower evolution of disability [20]. OPN seems to trigger clinical relapses through two mechanisms: 1) by stimulating expression of pro-inflammatory mediators in MS lesions; and 2) by inhibiting apoptosis of autoreactive immune cells. Intriguingly, anti-OPN antibodies (Ab) have been detected in EAE and their levels are increased by immunization with a plasmid containing the OPN cDNA [21]. A different and somehow opposite aspect is that OPN has been shown to enhance neuronal survival in the setting of ischemia and this neuroprotective activity is increased by thrombin cleavage of OPN [22, 23]. This might open new insights into the role played by OPN in the progressive phase of MS or in the context of other neurodegenerative diseases.

PARKINSON’S DISEASE AND EXTRAPYRAMIDAL DISORDERS Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra (SN) pars compacta of the midbrain, with subsequent deficit in dopamine synthesis [24]. From a neuropathological point of view, intraneuronal cytoplasmic aggregates of ␣-synuclein (Lewy bodies) are the hallmark of the disease [25]. The complex underlying biochemical events that eventually lead to apoptotic neuronal death have not been fully explained, and they include oxidative and nitrative stress, mitochondrial dysfunction, exci-


totoxicity, and abnormal protein aggregation [26–29]. Reactive microgliosis has been observed in PD as part of the inflammatory events occurring at a cellular and sub-cellular level, which are thought to be linked to neurodegeneration. Activated microglia in PD express inducible nitric oxide synthase (iNOS) producing nitric oxide (NO) and cyclo-oxygenase (COX)-1 and COX-2 [30] and a number of pro-inflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), IL-2, IL-4 and IL-6. Although it is still not clear whether inflammatory response is a protective reaction or a potential damaging event, changes in the cellular micro-environment may be responsible for neurodegeneration. In this context, the interest for OPN in PD comes from its anti-inflammatory and anti-apoptotic properties and its role in regulating iNOS transcription, reactive oxygen species production, and cytokines levels [31–33]. The role of OPN in PD has been studied both in animals and humans. In normal rats, OPN is expressed in the basal ganglia, especially in the SN [34], where its gene and mRNA expression are increased after glial cell activation following mechanical damage, intranigral injection of the bacterial endotoxin lipopolysaccharide (LPS) and loss of TH-positive cells caused by 6-hydroxydopamine (6-OHDA) [35, 36]. OPN is also expressed in non-human primate substantia nigra and in nigral dopaminergic neurons in man [37]. Iczkiewicz and coworkers demonstrated that OPN protein expression is decreased in surviving dopaminergic neurons in PD and is present in activated microglia but not in astrocytes. The same authors also observed a decreased expression of OPN in postmortem brains of subjects affected by atypical parkinsonism (multiple system atrophy and progressive supranuclear palsy), two conditions where a loss of dopaminergic neurons also takes place, thus suggesting that this phenomenon is not specific to PD [37]. Taken together, these observations suggest a potential role of OPN in neuroprotection, a hypothesis reinforced by the demonstration that the actions of OPN decline with advancing age, which is a major pre-disposing factor for PD [32, 38]. However, another study showed that following 1methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treatment, OPN knockout mice displayed less nigral cell death and a decreased glial response compared to wild-type mice [39]. The same authors showed that OPN serum and cerebrospinal fluid (CSF) levels are higher in PD patients than controls, with CSF levels positively correlated with concomitant dementia

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and serum levels correlating with more severe motor symptoms. Recently, it has been shown that the RGD-binding domain of OPN protects TH-positive cells against toxic insult induced by MPP+ and LPS, suggesting that this peptide fragment of OPN may be necessary for the survival of dopaminergic cells [40] in presence of a toxic insult. On the other hand, the work by Maetzler et al. [39] seems to indicate a possible disease-accelerating role of OPN in the MPTP animal model of PD. OPN has also been studied in Lewy body disease, a neurodegenerative disorder characterized by cognitive decline, extrapyramidal features, visual hallucinations, and fluctuating levels of consciousness. Similarly to PD, higher levels of OPN in the CSF and serum have been observed in this disease as compared to controls, and Lewy bodies have been demonstrated to be OPN-positive on immunostaining. Moreover, a single nucleotide polymorphism of the OPN gene seems to contribute to the susceptibility to the disease [41].

ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is the most common type of dementia world-wide and it mostly affects individuals aged over 65 years. At a neuropathological level, it is characterized by progressive neurodegeneration with extensive loss of neurons and synapses. In AD brains, there is a characteristic deposition of extracellular amyloid-␤ peptides aggregates in senile plaques as well as the formation of intracytoplasmic neurofibrillary tangles, which consist of abnormally phosphorylated tau protein. Several studies have shown an important role of inflammatory processes such as microglial activation and local upregulation of acute-phase proteins, complement, cytokines, and other inflammatory mediators mainly around amyloid plaques, especially in the early stages of the disease [42, 43]. For this reason, the role of a number of proteins involved in inflammatory responses, including OPN, has been investigated in AD. In normal rats, OPN mRNA has been localized to neurons of the olfactory bulb, cerebellum, and brainstem [44], with higher expression in the pons and medulla than the midbrain [45]. In the human brain, Wung and collaborators localized OPN to the cytoplasm of pyramidal neurons of the CA1 region of the hippocampus of subjects affected by

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AD, finding a 41% increase in OPN expression in this neuronal population compared to age-matched controls [46]. The same authors also showed a significant positive correlation between OPN staining intensity in the hippocampus and both amyloid-␤ load and age, suggesting that increased OPN expression is probably a response to age-related neurodegeneration, which is accelerated in AD, and to the neuropathological changes that occur in this disease. In this scenario, OPN may act in the remodeling processes that take part in AD brain along with widespread neuronal loss. It has in fact been shown that OPN upregulates myelination and remyelination in in vitro cellular cultures [47]. OPN expression has been demonstrated to be upregulated in two additional animal models of neurodegneration. Wirths et al. [48] used the A␤PP/PS1 KI mice (an animal model of AD with severe pathological alterations) to analyze some inflammatory and oxidative stress markers and observed an increased expression of OPN on the mRNA and protein level that colocalized to the neuritic component of extracellular plaques at the age of six months, namely in the symptomatic phase of animals’ life when they manifest symptoms and the typical neuropathological changes of AD. More recently, OPN has been shown to be the most strongly upregulated cytokine in activated microglia following hippocampal kainic acid injection in the Senescence-accelerated mouse prone 10 (SAMP10), a mouse strain characterized by accelerating senescence and early cognitive decline. OPN upregulation was accompanied by upregulation of CD44, to which OPN binds to exert its anti-apoptotic activity in response to GM-CSF [49]. As the complex OPN-CD44 is important in neuroprotection and remodeling, it is possible that the increased expression of OPN represents an attempt to react against neuronal damage in AD. OPN has recently been proposed as a biomarker to predict the progression of mild cognitive impairment (MCI) to overt AD. In fact, Simonsen and colleagues [50] have identified, by means of proteomic analysis of CSF samples, a panel of biomarkers that were differentially expressed in patients with MCI who progress to AD as compared to patients who remain stable over time and healthy controls. Among these potential biomarkers, a phosphorylated C-terminal fragment of OPN was increased in patients with MCI progressing to AD as compared to the other groups, suggesting that neuroinflammation is more marked in the early clinical stages of the disease and the upregulation of OPN may reflect these phenomena.

Taking into account these observations, we hypothesized that OPN was increased in the CSF of AD patients, reflecting its upregulation mostly in the early stages of neurodegeneration. Consistently with this hypothesis, we demonstrated that OPN levels are increased in AD subjects as compared to controls and its levels are more markedly raised in the early stages of the disease (≤2 years) and correlate with cognitive decline expressed with a Mini-Mental Status Examination (MMSE) score, being higher in patients with a MMSE score >23 [51]. In the same paper, no differences in OPN serum levels were detected in AD patients compared to controls and frontotemporal dementia. FRONTOTEMPORAL DEMENTIA Frontotemporal dementia (FTD) is the second most common type of presenile dementia worldwide, mainly affecting individuals aged 45–65 years. FTD cases can be either sporadic or genetic, and familial cases account for 20–30% of patients. Five genes (MAPT, GRN, VCP, CHMP2B, FUS) are known to cause the disease, that is extremely heterogeneous in terms of age of onset and clinical presentation [52]. The role of OPN in FTD has not been extensively investigated and limited data are available. We previously assessed OPN serum levels in 46 FTD patients and found no differences with controls or AD patients. As previously mentioned, OPN CSF levels were much higher in AD cases compared to FTD, whereas no differences were found between FTD cases and controls (p = 0.2). Mattson et al. [53] stratified a group of 24 FTD patients according to the CSF levels of neurofilament light chain (NF-L), a protein reflecting the degree of axonal degeneration in the CNS. Using a proteomic approach with SELDI-TOF mass spectrometry followed by chromatographic purification, they identified 3 peaks corresponding to a C-terminal fragment of OPN as well as its mono- and diphosphorylated forms. The correlation between extensive axonal damage and increased concentration of OPN in the CSF led the authors to suggest a role of OPN in the neurodegenerative processes that take part in FTD, although its role in this disorder still needs to be clarified. CONCLUSIONS Since its discovery, the role of OPN has been investigated in a number of physiological and pathological


processes. The interest for this protein in neurological diseases initially rose from the observation that OPN was highly expressed in demyelinating plaques in MS and that OPN-KO mice did not develop the typical neuropathological changes of EAE. OPN has been considered to play an important role in the modulation of inflammation and apoptosis, by inhibiting some anti-apoptotic proteins. It is a well-established concept that inflammatory responses are also present in progressive neurodegenerative disorders such as PD and AD, where they may act as a double-edged sword, leading on the one hand to neuronal toxicity and death and exerting on the other hand a potentially neuroprotective function. A neuroprotective role of OPN as an anti-apoptotic factor has been postulated in PD due to its reduced expression in the substantia nigra of patients, although OPN-KO mice seem to display a reduced degree of neurodegeneration. As a chemoattractant, OPN can attract macrophages in the site of injury to clear cellular debris and activate astrocytes with subsequent synthesis of neurotrophic factors. The different outcomes of experimental studies in rats with regard to the possible role of OPN in the degeneration of dopaminergic neurons may in part be attributed to differences in animal models and humans. OPN has been localized also to key areas of the brain that degenerate in AD, where it is upregulated in the initial stages of the disease (as reflected by its CSF levels) and correlate with the amyloid-␤ load. According to the available data, it seems that OPN may be increased in subjects displaying a more pronounced inflammatory response in the early stages of the disease, which may lead to a progression of the initial cognitive deficit and to overt symptoms. For this reason OPN has been proposed as a biomarker to individuate MCI subjects at risk of developing AD. Similarly, OPN plasma levels are raised also in the CSF of HIV positive individuals and its plasma concentration increases prior to the development of HIVinduced CNS dysfunction ultimately leading to HIVassociated dementia [54]. The correlation between increased OPN plasma levels and the onset of cognitive symptoms has been clearly demonstrated also in the animal model of HIV (SIV-infected Rhesus monkeys). In conclusion, OPN is a key protein in several physiological and pathological processes and, thanks to its role in neuroinflammation, it may be considered a potential target for future therapies. Further studies are needed to unravel the complexity of the biological background responsible for the development of

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