The International Journal of Biochemistry & Cell Biology 60 (2015) 130–138

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Review

Urocortin – From Parkinson’s disease to the skeleton K.M. Lawrence a,b,∗ , T.R. Jackson a,b , D. Jamieson c,d , A. Stevens e , G. Owens a,b , B.S. Sayan a,b , I.C. Locke f , P.A. Townsend a,b a

Faculty Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, St Mary’s Hospital, Research Floor, Oxford Road, Manchester M13 9WL, UK Manchester Centre for Cellular Metabolism, FMHS, UoM, M13 9WL, UK c Faculty of Life Sciences, Michael Smith Building, University of Manchester, M13 9WL, UK d Biorelate Ltd, Manchester, UK e Faculty of Medical and Human Sciences, University of Manchester and Royal Manchester Children’s Hospital, Manchester M13 9WL, UK f Department of Biomedical Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK b

a r t i c l e

i n f o

Article history: Received 30 September 2014 Received in revised form 12 December 2014 Accepted 13 December 2014 Available online 23 December 2014 Keywords: Urocortin Apoptosis Parkinson’s disease Arthritis Osteoporosis

a b s t r a c t Urocortin (Ucn 1), a 40 amino acid long peptide related to corticotropin releasing factor (CRF) was discovered 19 years ago, based on its sequence homology to the parent molecule. Its existence was inferred in the CNS because of anatomical and pharmacological discrepancies between CRF and its two receptor subtypes. Although originally found in the brain, where it has opposing actions to CRF and therefore confers stress-coping mechanisms, Ucn 1 has subsequently been found throughout the periphery including heart, lung, skin, and immune cells. It is now well established that this small peptide is involved in a multitude of physiological and pathophysiological processes, due to its receptor subtype distribution and promiscuity in second messenger signalling pathways. As a result of extensive studies in this field, there are now well over one thousand peer reviewed publications involving Ucn 1. In this review, we intend to highlight some of the less well known actions of Ucn 1 and in particular its role in neuronal cell protection and maintenance of the skeletal system, both by conventional methods of reviewing the literature and using bioinformatics, to highlight further associations between Ucn 1 and disease conditions. Understanding how Ucn 1 works in these tissues, will help to unravel its role in normal and pathophysiological processes. This would ultimately allow the generation of putative medical interventions for the alleviation of important diseases such as Parkinson’s disease, arthritis, and osteoporosis. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urocortin and Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urocortin, arthritis and osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Urocortin and rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Urocortin and osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Urocortin and osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future perspectives for urocortin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: Ucn 1, urocortin; CRF, corticotropin releasing hormone; CRF-R, corticotropin releasing hormone receptor; PD, Parkinson’s disease; SN, substantia nigra; GSK-3␤, glycogen synthase kinase- 3␤; HDAC, histone deacetylase; RA, rheumatoid arthritis; OA, osteoarthritis; OP, osteoporosis; Ch, chondrocyte; Oc, osteoclast; Ob, osteoblast. ∗ Corresponding author. Tel.: +44 01617017559x17559; fax: +44 01617016919. E-mail address: [email protected] (K.M. Lawrence). http://dx.doi.org/10.1016/j.biocel.2014.12.005 1357-2725/© 2014 Elsevier Ltd. All rights reserved.

K.M. Lawrence et al. / The International Journal of Biochemistry & Cell Biology 60 (2015) 130–138

1. Introduction Peptides originally discovered in the brain and subsequently demonstrated to have a physiological role there, were often classified under the umbrella of “neuropeptide”, implying that these molecules were specific to the brain. Although many have origins in the brain, they can also be released, or induce the release of related factors into the circulation, where they can exert their effects on diverse peripheral tissues. Recently, many of these molecules have been found to also exist in peripheral tissues, making the term neuropeptide redundant (Iversen et al., 1978). First cloned in 1981 by Spiess et al. (1981), CRF is an example of such a peptide. This 41 amino acid peptide was originally described as a hypothalamic hormone, responsible for the release of ACTH from the anterior pituitary gland, which then enters the circulation and ultimately causes the release of cortisol from the adrenal cortex (Smith and Vale, 2006). The original proposed role of CRF was as a key activator of the hypothalamus-pituitary-adrenal (HPA) axis and as such has a crucial role in the stress response. It had long been known that CRF binds to two different G-protein coupled receptors, CRF receptor 1 (CRF-R1) and 2 (CRF-R2), both the product of independent genes and subject to extensive alternative RNA splicing (Hauger et al., 2003; Perrin and Vale, 1999). However, investigators soon identified certain anatomical and pharmacological anomalies with this relationship. Firstly, there was a very poor correlation between the sites of expression of CRF-R2 in the brain and CRF itself and secondly, CRF had a relatively low binding affinity for CRF-R2. Both pieces of evidence suggested the existence of at least one more related ligand and in 1995 Vaughan and colleagues used homology cloning based on the sequence of CRF to identify a second member of this family, the 40 amino acid peptide, Ucn 1 (Vaughan et al., 1995). Since then, two further paralogues of Ucn 1 have been isolated; Ucn 2 (Human Stresscopin Related Peptide), and Ucn 3 (Human Stresscopin), which are composed of 38 and 39 amino acids respectively (Hsu and Hsueh, 2001). Radioligand binding studies have revealed that CRF and Ucn 1 have affinity for both receptor subtypes, but Ucn 1 is significantly more potent than CRF on CRF-R2, whereas Ucn 2 and 3 bind exclusively to CRF-R2 (Perrin and Vale, 1999). These peptides are evolutionary ancient molecules having representatives in lower vertebrates such as sauvagine in amphibia and urotensin in fish (Lovejoy, 2009; Lovejoy and Balment, 1999). In fact, the name urocortin is an amalgam of fish urotensin and corticotropin. This system is completed by corticortropin releasing factor-binding protein (CRF-BP), which acts as a pseudo-receptor for both CRF and Ucn 1 (Behan et al., 1996; Seasholtz et al., 2002), suggesting that this family of receptors and ligands may be self-regulating. These peptides and proteins were originally found in the brain and played an important role in the regulation of the HPA axis and the stress response, however, their specific functions in the stress response differ. CRF actions are stressful, whereas those of Ucn 1 are stress-coping (Reul and Holsboer, 2002). The CRF family peptides are now known to be localised to every major organ of the body where they exert local actions on tissues and cells in both an autocrine and paracrine manner. These peptides are highly pleiotropic, having wonderfully diverse modes of action resulting from a combination of factors depending on the tissue type. Firstly, the peptides display markedly different affinities for the two classes of CRF receptors. Secondly, they also exhibit a remarkable degree of receptor signalling promiscuity (Brar et al., 2002; Grammatopoulos et al., 2000; Graziani et al., 2002; Lawrence and Latchman, 2006) (Fig. 1). This is facilitated by their ability to couple to multiple Gproteins, even within the same cell. The consequence of this is the regulation of diverse intracellular networks that involve numerous effectors such as cAMP, intracellular ions, and an array of protein kinases, ultimately resulting in altered gene expression (Barry

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et al., 2010; Lawrence et al., 2002). Common signalling pathways utilised by these peptides include mitogen-activated protein kinase (MAPK) pathways, in particular the extracellular signal-regulated kinases (ERKs). ERK1/2 constitute a widely conserved family of serine threonine protein kinases involved in many cellular functions such as cell proliferation, cell differentiation, cell movement, and cell survival (MacCorkle and Tan, 2005). As a result of their multiple cellular activities, it is becoming apparent that these peptides are involved in numerous normal and pathological states and that by understanding their modes of action in various tissues, it may be possible to manipulate this system for clinical gain and to develop novel treatments for numerous CNS and peripheral disorders. Many of the well-known actions of Ucn 1 such as its role in mood disorders, or its effects on peripheral systems such as the cardiovascular and immune systems, have been extensively reviewed elsewhere (Baigent, 2001; Davidson and Yellon, 2009; Fekete and Zorrilla, 2007; Gravanis and Margioris, 2005; Yang et al., 2008). The aim of this review therefore, is to focus on some of the lesser known effects of Ucn 1, such as its role in neurodegeneration in Parkinson’s disease and disorders of the skeletal system. These examples are selected with the intention of highlighting how the understanding of Ucn 1’s mechanisms of action is expanding further, along with the diverse therapeutic potential of Ucn1 itself, Ucn 1 mimetics, or Ucn 1 receptor antagonists.

2. Urocortin and Parkinson’s disease Although the exact cause of Parkinson’s disease (PD) is unknown, the most consistent anatomical feature is severe degeneration of the dopaminergic neurones of the Substantia Nigra (SN) and striatum (Foltynie and Kahan, 2013; Samii et al., 2004), which in humans, results in characteristic motor abnormalities such as tremor, rigidity, hypokinesia, and postural instability (Meissner, 2012). Histologically, these neurones exhibit a characteristic cocktail of toxic cellular inclusions; Lewy bodies, neurofibrillary tangles, and an enrichment of ␣-synuclein (Breydo et al., 2012; Forno, 1996; Lei et al., 2010). It has been estimated that up to 80% of neuronal death occurs in the dopaminergic SN pars compacta before clinical manifestations of PD appear. Although the precise cause of the inevitable neuronal demise remains nebulous, potential contributing factors include glutamatergic excitotoxicity (Duty, 2010), elevated free-radical production (Surendran and Rajasankar, 2010), neuroinflammatory events (Tufekci et al., 2012), and overexpression of Parkinsonian genes, in particular the ubiquitin ligase Parkin (Springer and Kahle, 2011). Whatever the cause of this neuronal cell death, it is thought to be mainly apoptotic in nature (da Costa and Checler, 2011; Perier et al., 2012; Venderova and Park, 2012). Clearly, a compound which possesses the ability to prevent cellular apoptosis, free radical damage, and inflammation would be a good candidate as a protective agent against the ravages of PD. These three prerequisites have been found for Ucn 1 in other tissues (Lawrence and Latchman, 2006; Barry et al., 2010; Baigent, 2001). The abundant expression of both Ucn 1 and its cognate receptors in dopaminergic neurons and astroglia of the SN, suggests that Ucn 1 plays a role in PD pathophysiology (Yamamoto et al., 1998). However, at present, there is no data concerning altered expression levels of Ucn 1 in PD. The most convincing in vivo study implicating Ucn 1 as a neuroprotective agent in PD was conducted by Abuirmeileh (Abuirmeileh et al., 2007a,b, 2008, 2009), using the classical 6-hydroxydopamine (6-OHDA) lesion, and lipopolysaccharide (LPS) induced pro-inflammatory toxicity models to generate parkinsonism in rats. Upon stereotactic targeting to dopaminergic neurones of the SN, both insults increased the characteristic apomorphine induced circular motor activity, known to accompany neuronal ablation, with an associated loss of

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Fig. 1. Schematic representation of the receptor selectivity and intracellular targets for the Ucns. While Ucn 1 acts via both CRF-R1 and CRF-R2, Ucn 2 and Ucn 3 are selective for CRF-R2. The Ucn1-CRF-R1 network is depicted in red, Ucn 1-CRF-R2 represented by green, Ucn 2-CRF-R2 is shown in pink, and Ucn3-CRF-R2 in orange. Ucn 1 can also inhibit HDACs and activate Kir6.1; the CRF receptor subtype responsible for these effects are as yet unknown (blue). HDAC: histone deacetylase, GSK3␤: glycogen synthase kinase 3␤, AKT: RAC-alpha serine/threonine-protein kinase1, PI3K: Phosphatidylinositol-4, 5-bisphosphate 3-kinase, P42/44: Mitogen-activated protein kinases, kir6.1: KATP sensitive potassium channel 6.1, TRPC1: Transient receptor potential canonical1, Ca2+ channels: voltage dependant calcium channels. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2. Mechanisms of neuroprotection by Ucn 1. Stimuli such as glutamate excitation or free radicals are potentially directly neurotoxic to SN neurones. Ucn 1, which is highly expressed in the dopaminergic neurones will activate predominantly CRF-R1 on the neurone in an autocrine/paracrine protective manner and activate stress induced neuroprotective signals via cAMP. Pro-inflammatory stimuli such as LPS target and activate the pro-inflammatory cells of the brain the microglia, producing and releasing predominantly TNF␣ which if unchecked, will cause neuronal cell death. The extent of inflammation must be tightly controlled to minimise neuronal damage while maximising the anti-pathogenic effect. Neuroprotection by Ucn 1 in this case is a paracrine effect, whereby neuronal release of Ucn 1 will deactivate microglia and reduce the TNF␣ production and release, via CRF-R2. These effects are produced by the activation of the Akt/GSK-3 pathway.

tyrosine hydroxylase (TH). Significantly, the addition of Ucn 1 reduced all of these indicators of cell death, suggesting that Ucn 1 protects against direct neurotoxicity and cell death caused by LPS induced neuroinflammation (Abuirmeileh et al., 2009). Remarkably, and of potential clinical relevance, was the finding that as

well as protecting cells of the SN prior to an insult, Ucn 1 also caused a full recovery from 6-OHDA and LPs induced lesions, after the insult had occured. This suggests that Ucn 1 is also able to rescue previously damaged dopaminergic neurons. Whether this is the result of a cytoprotective action of Ucn 1 against neurotoxins, or

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neuro-inflammatory insults, or a stimulation of neurogenesis in the damaged nigrostriatal system is as yet unclear. Interestingly, these findings could not be replicated with the selective CRF-R2 specific ligand Ucn 3, suggesting that Ucn 1, in this case, is acting via CRF-R1 receptors (Abuirmeileh et al., 2009). Its effect was also abrogated by the specific type 1 receptor antagonist, NBI 27914. This is the same receptor subtype which has been shown to be anti-inflammatory in the periphery (Gravanis and Margioris, 2005). Although cytoprotective effects of Ucn 1 are well known in other tissues, its mechanism of action here is far from clear. A clue to the mechanism of action of Ucn 1 on cells of the SN may be found in the data from Kim et al. (2010), who showed that degeneration of mesencephalic dopaminergic neurons, (which undergo spontaneous degeneration with age) treated with the Parkinson mimetic neurotoxin MPP+ , could also be rescued by Ucn 1 addition. Furthermore, blockade of this action by a Ucn 1 depleting antibody, accelerated the neuronal degeneration. The mechanism of action here, appeared to be through the activation of cAMP-dependent pathways. Elevation of intracellular cAMP levels is known to promote the survival of a variety of central and peripheral neuronal populations, including dopaminergic neurons (Chalovich et al., 2006). Furthermore, various cAMP-enhancing reagents mimicked the effect of Ucn 1, while inhibitors for protein kinase A (PKA) blocked this effect, strongly implicating the involvement of cAMP-PKA pathway in this neuroprotection. Downstream from cAMP, Ucn 1 was found to exert its effects by inhibition of glycogen synthase kinase-3␤, (GSK-3␤), through phosphorylation of serine 9. GSK-3␤, is an enzyme intimately associated with AKt and the Wnt signalling pathway and ␤ Catenin transcriptional events (Huang et al., 2011; Stamos and Weis, 2013). GSK-3␤ activity appears to have an inverse correlation with neuronal viability (Jeon et al., 2013; Noh et al., 2009; Petit-Paitel et al., 2009), and Ucn 1-mediated neuroprotection was mimicked by 803-mts, a selective peptide inhibitor of GSK-3␤, but was blocked by the activator, cPAF, suggesting that inhibition of GSK-3␤ is responsible for the action of Ucn 1. Emerging evidence also suggests that GSK-3␤, is an important modulator of apoptosis, with the inactivation of GSK-3␤ shown to mediate cAMP-evoked neuroprotection from serum deprivation and a lowering of the KCl concentration in rat cerebellar granule neurons (Liang and Chuang, 2007). Consistent with this, blocking the cAMP/PKA pathway resulted in reduced GSK-3␤, phosphorylation and increased cell death, further suggesting that Ucn 1-induced GSK-3␤ phosphorylation-dependent neuroprotection is mediated by a rise in intracellular levels of cAMP. As well as its effects on GSK-3␤, an additional contribution to Ucn 1-induced neuroprotection, was found to be associated with its ability to directly block the activity of the enzyme Histone deacetylase 3 (HDAC 3) in neuronal cells (Huang et al., 2011; Tang et al., 2013). HDACs catalyse the removal of acetyl groups from lysine residues of histones resulting in a tighter chromatin conformation and diminished transcription and have a role in neuronal protection (Bardai et al., 2012; Dietz and Casaccia, 2010; Kelly et al., 2002; Ren et al., 2004). Of note, is the additional evidence that HDAC inhibitors (VPA, SB, and TSA) also cause histone H3 hyper acetylation and protect neurons against glutamate-induced excitotoxicity. Several lines of investigation support the notion that HDAC inhibition suppresses ischaemia, or excitotoxicity-induced neuronal caspase-3 activation (Uo et al., 2009) and Huntingtin polyglutamine-induced toxicity (Bates et al., 2006). Significantly, HDAC inhibitors were found to rescue ␣-synuclein mediated toxicity in a Drosophila model of PD (Bates et al., 2006; Leng and Chuang, 2006; St Laurent et al., 2013). These studies all indicate the potential of Ucn 1 to act as a neuroprotective factor by preventing the spontaneous demise of dopaminergic neurons and inhibiting caspase activity. This implies that dopaminergic neuronal derived Ucn 1 and its receptors, might be involved in an autocrine/paracrine protective signalling

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mechanism. Analysis of brain tissue sections, for the presence of the Ucn system, not only identified Ucn 1 and its receptors in neuronal cells, but also a strong signal for the presence of CRF receptors in microglial cells (Wang et al., 2007), suggesting the possibility for a wider autocrine/paracrine network. Microglia are the major inflammatory cells present in the brain and principally responsible for the production of the pro-inflammatory cytokine, TNF-␣, in response to LPS toxicity. This mechanism, may therefore be involved in neuroinflammation, which is becoming widely accepted as a key factor in the aetiology of PD. Thus, Ucn 1 may regulate cellular communication between dopaminergic neurons and microglia, thereby preventing cell damage by reducing the massive astrogliosis, which arises in the SN as a result of LPS-induced toxicity (Hoban et al., 2013) (Fig. 2). One further exciting possible explanation for the effect of Ucn 1 on dopaminergic neurones is that Ucn 1 is instigating de-novo neurogenesis, presumably from recruited stem cells, as has been postulated in other studies (Huang et al., 2012). It is possible that Ucn 1 affects a regrowth and remodelling of surviving dendrites as observed by Gounko et al. (2013). Whatever the exact mechanism of action of Ucn 1 in neuronal regulation/protection/regeneration, it is clear that endogenous Ucn 1 and its receptors are involved in a complex network of both autocrine and paracrine events within the CNS. Clearly, much work still remains if we are to uncover the precise mechanism of action of Ucn 1 and its role in the aetiolgy and or treatment of PD. A deeper understanding of its mechanism of action will enable the development of novel treatments/prophylactics to offset neuronal degeneration in PD and perhaps wider CNS degenerative disorders. 3. Urocortin, arthritis and osteoporosis The extraordinary diverse localisation and functions of the Ucn system has recently been extended further, following the documentation of the Ucn system component expression and function in skeletal tissues. Several prevalent skeletal diseases occur in humans including rheumatoid arthritis (RA), osteoarthritis (OA) and osteoporosis (OP), resulting in the degradation of cartilage and bone, (primarily long bones) respectively. We will consider the role of Ucn 1 in the pathology of each of these three degenerative disorders in turn. 3.1. Urocortin and rheumatoid arthritis RA is an autoimmune disease of unknown aetiology that leads to chronic inflammation in the joints and subsequent destruction of the cartilage and erosion of the surrounding bone (Schneider and Kruger, 2013). The initial stages of RA involve multiple steps, which can be divided into two main phases; autoimmunity, and the later events associated with the evolving immune and inflammatory responses. Although the contribution of T-helper cells (specifically the Th1 responses) in RA is uncertain, several studies in animal models indicate a pathogenic role for Th1-derived cytokines (Kokkonen et al., 2010). Th1 cells react to components of the synovium, release pro-inflammatory cytokines and chemokines, as well as promoting macrophage and neutrophil infiltration and activation. High levels of the inflammatory mediators, (cytokines, free radicals), produced by infiltrating inflammatory cells, have a critical role in joint damage in RA (Shah et al., 2011; Yu et al., 2012). The first suggestion of a potential role for Ucn 1 in skeletal disorders, came when expression of Ucn 1 mRNA and CRF receptor immunoreactivity was demonstrated in the synovia. This included the synovial lining cell layer, subsynovial stromal cells, endothelial cells, and mononuclear inflammatory cells. From an arthritis model of RA, it was found that Ucn 1 provided a highly effective therapy by strikingly reducing the two deleterious components of the

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disease; the autoimmune response, and the inflammatory response (Gonzalez-Rey et al., 2007). Treatment with Ucn 1 decreased both the presence of auto-reactive Th1 cells in the peripheral circulation and in the joint. This was perhaps caused by the generation and/or activation of IL10/TGF-1␤ producing Treg cells which have the capacity to suppress the autoreactive response and to restore immune tolerance. It is therefore plausible that deactivation of resident and infiltrating macrophages, is a major mechanism involved in the action of Ucn 1 in joints of RA and OA patients (Kohno et al., 2001; Perez-Garcia et al., 2011; Uzuki et al., 2001). Not only was Ucn 1 present, but it appeared to be a biomarker for RA, as its expression was significantly greater in RA than OA and appeared to correlate with the extent of inflammatory infiltrates. Ucn 1 and its receptors were detected in several types of immune cells, including macrophage/monocytes and T cells (Bamberger et al., 1998; Souza-Moreira et al., 2011). In addition Ucn 1 caused IL-1␤ and IL-6 secretion by human peripheral blood mononuclear cells in vitro. These data would suggest that Ucn 1 is present in peripheral inflammatory sites, such as the rheumatoid synovium and may act as an autocrine/paracrine immune-inflammatory mediator in RA patients via CRF R1. Therefore, modulation of Ucn 1 signalling through CRF-R1 antagonism may alleviate RA effects and promote clinical benefit. In a separate in vivo study, Ucn 1 treatment strongly down-regulated the production of a number of pro-inflammatory cytokines in the inflamed joint including TNF-␣, IFN-␥, IL-6, IL-1␤, and IL-12, and increased the levels of the antiinflammatory cytokines IL-10, and TGF-␤, which ameliorated the disease. This may be explained by the ability of Ucn 1 to induce cAMP, as several cAMP inducing agents have been found to be potent anti-inflammatory factors (Gerlo et al., 2011). cAMP acts here by down-regulating the activation of the transcription factor NF-␬␤, a factor essential for the transcriptional activation of most of the inflammatory cytokines, chemokines, and co-stimulatory factors. The apparent discrepancy in the role of Ucn 1 in RA, may be explained by the presence of both CRF-R1 and R2 receptors in joint tissues and infiltrating cells. Here, Ucn 1 may have a potential antiinflammatory, or cytoprotective function, mediated by CRF-R2. However, in arthritis, its pro-inflammatory action, through CRF-R1mediated effects, appears to dominate. Thus the role of Ucn 1 in this context may be receptor subtype specific and that recent developments in the synthesis of highly selective CRF receptor antagonists may both shed further light on the complex role of Ucn 1 in RA and may also prove to be a potent treatment for this disease. 3.2. Urocortin and osteoarthritis Whilst the inflammatory process clearly contributes to the pathogenesis of OA, particularly in the latter stages, the disease process is very different to that of RA. Central to the development of OA, is the damage and degradation of articular cartilage, as a result of excessive long term ‘wear and tear’ on the joints. Articular cartilage is responsible for covering opposing subchondral bones and allows normal joint function by providing a smooth load absorbing surface, enabling pain free joint motility. The connective tissue of cartilage is produced and maintained by articular chondrocytes and in healthy cartilage matrix, these are the only cell type present (Muir, 1995). Therefore, chondrocytes are crucial for normal joint integrity, maintaining the structure and mechanical strength of the cartilage. Furthermore, the pathological transformation of cartilage associated with OA, have been attributed to a reduction in the number of healthy, active chondrocytes, occurring primarily in the superficial zone of the cartilage without distinct changes in the middle or deep zones (Kobayashi et al., 2003; Loeser, 2009). During OA, chondrocyte death occurs by a unique form of apoptosis/programmed cell death termed chondroptosis. Although it

resembles classical apoptosis in many ways, subtle differences can be seen such as the absence of membrane ‘blebbing’ (Roach et al., 2004). Although it is now well established that chondrocyte cell death contributes to progressive articular cartilage damage and a loss of joint function, the stimuli involved are multifactorial. Several locally occurring factors have however been implicated, including nitric oxide (NO) (Blanco et al., 1995), oxygen free radicals (Li et al., 2012), TNF-␣, IL-1 (Carames et al., 2008) and Fas ligand (Kim et al., 2003). NO, in particular, is present in significant quantities within OA joints in vivo (Amin et al., 1995; Farrell et al., 1992) and elevated levels of NO in the cartilage and synovial fluid, may be a result of excess production, in response to a variety of mechanical and chemical stresses. Recent work by (Intekhab-Alam et al., 2013), found that Ucn 1 was highly expressed in a human chondrocyte cell line C-20/A4 and intriguingly found that both CRF-R1 and CRF-R2 are present in these cells, both by PCR and Western immunoblotting (Intekhab-Alam et al., 2013). By using either the pan CRF receptor antagonist, ␣-helical CRF, or a Ucn 1depleting antibody, it was demonstrated that Ucn 1 was crucial for the maintenance of chondrocyte survival under basal conditions. Furthermore, when cells were challenged with a pro-apoptotic insult commonly found in OA, such as NO, Ucn 1 expression was significantly up-regulated, suggesting an autocrine/paracrine regulation of cell survival. When these cells were treated with the NO donor (S)-Nitroso-N-acetylpenicillamine (SNAP), exogenous Ucn 1 was highly effective at preventing apoptosis. The reason for both CRF receptor subtypes being present on chondrocytes is unclear, especially as Ucn 1 has affinity for and can activate both receptors. However, because of receptor promiscuity in Ucn 1 receptor signalling, it may be that these receptors are coupled to different second messenger systems within chondrocytes. This then exposes the possibility that one type of receptor may be responsible for the chondrocyte maintaining effect of Ucn 1, while the other is involved in its anti-apoptotic effect after a pro-apoptotic stimulus. Although this is the only study of its kind thus far, it is clear that an agent which is both crucial for not only chondrocyte maintenance, but also protective against pro-apoptotic stimuli, merits further investigation as a potential prophylactic against cartilage degradation. 3.3. Urocortin and osteoporosis Unlike RA and OA, OP does not involve an inflammatory component or a loss of crucial cells responsible for tissue deposition and maintenance. Instead an uncoupling occurs between the cells that deposit new bone, the osteoblast (Ob), and those responsible for bone resorption, the osteoclast (Oc), resulting in a net increase in Oc resorptive activity (Boyce et al., 2012; Chambers, 2010). The increase in net bone degradation in OP is reliant upon three prerequisites. Firstly, increased de-novo differentiation of Oc from bone marrow derived haemopoetic stem cells, originating from the monocyte macrophage lineage. This occurs only in the presence of receptor activator of NFk-B ligand (RANKL) and macrophage colony stimulating factor (M-CSF). Secondly, an increase in the activity of extant Oc, involving increased bone resorption and thirdly migration of Oc to unresorbed areas of bone. Remarkably, a recent paper by Combs et al. (2012), has demonstrated that Ucn 1 can inhibit all of the above functions. Firstly, Ucn 1 treatment inhibits Oc maturation into large multinucleated tartrate resistant acid phosphatase (TRAP) positive cells, from precursor cells, as well as the down-regulation of the expression of several Oc marker gene expression levels, including calcitonin receptor (CT-R), Cathepsin K (Cath K), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). All of which play important roles in Oc function. Furthermore, Ucn 1 was found to potently inhibit Oc

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Fig. 3. The highly complex scenario at the cartilage/bone interface involving members of the Ucn system. Chondrocytes express Ucn 1 and both CRF-R1 and CRF-R2. Ucn 1 can have an autocrine effect on chondrocytes Via CRF-R1 and/or CRF-R2 which is chondroprotective, or a paracrine effect on osteoclasts which is anti-resoptive via CRF-R2. Osteoclasts express Ucn 1 and CRF-R2. Here Ucn 1 could have an autocrine effect on osteoclasts via CRF-R2 to control resorptive activity and motility, or a paracrine effect on chondrocytes controlling their survival via CRF-R1 or CRF-R2. Osteoblasts do not express Ucn 1, CRF-R1, or CRF-R2. However they express large amounts of CRF-BP, the release of which, by as yet unknown mechanisms will control local levels of Ucn 1 and regulate chondrocyte and osteoclast survival/activity.

resorption, in the nanomolar range, based on two in vitro measurements of resorptive activity; actin ring formation, and the number of resorption pit excavations on bone slices (Combs et al., 2012). As well as these highly specific effects, Ucn 1 was also found to inhibit Oc motility within thirty minutes of application. These characteristics of Ucn 1 fulfil most of the criteria demanded of an effective antiresorbtive agent. The second messenger pathway by which Ucn 1 achieved these goals was not fully addressed. However, it was determined that the

end result of Ucn 1 treatment was the inhibition of an ion channel. Using direct whole cell patch recordings to characterise the channel type, they found that the channel properties effected by Ucn 1, based on channel amplitude inactivation and gating kinetics, were those of a constitutively active Transient Receptor Potential Channel Canonical 1 type (TRPC1) cation channel, which was also found to be highly expressed both, at the mRNA, and protein levels, in mature osteoclasts (Combs et al., 2012). These channels are involved in calcium signalling and although found in the plasma

Table 1 Selected enriched disease co-occurrence with Ucn 1 publications. Disease concepts were sourced from the disease oncology (PMID:22080554) and an in-house database. Enrichment p values were calculated using Fisher’s Exact test. Name

Disease id

P val

Generic out

Sensorineural hearing loss Nonsyndromic deafness Ischemia Hypoxia Lactic acidosis Obesity Mitochondrial disease Diabetes mellitus Anorexia nervosa Mitochondrial myopathy Enlarged vestibular aqueduct Irritable bowel syndrome Melas syndrome Multiple endocrine neoplasia Hyperglycemia Osteosarcoma Syndrome Myopathy Oculomotor paralysis Rheumatoid arthritis Parkinson’s disease Myocardial infarction Ischaemic heart disease Osteoarthritis Anxiety disorder Eating disorder Bone disease Asthma Bipolar disorder

DOID:10003 DOID:0050563 DOID:326 BIOR:10 DOID:3650 DOID:9970 DOID:0080013 DOID:9351 DOID:8689 DOID:699 DOID:0050332 DOID:9778 DOID:3687 DOID:3125 DOID:4195 DOID:3347 DOID:225 DOID:423 DOID:539 DOID:7148 DOID:14330 DOID:5844 DOID:3394 DOID:8398 DOID:2030 DOID:8670 DOID:0080001 DOID:2841 DOID:3312

1.01E−50 6.98E−33 2.35E−30 1.58E−20 5.34E−16 7.38E−16 1.63E−14 3.59E−11 1.29E−10 2.3867E−10 7.3725E−10 1.1993E−09 2.4806E−09 5.8441E−09 8.7704E−09 2.1754E−08 7.3491E−08 8.4742E−08 9.5858E−08 9.918E−06 1.4524E−05 5.1168E−05 0.00022326 0.00394188 0.00539521 0.03845575 0.07286941 0.14541938 0.22229177

9494829 9503071 9361497 9414855 9497419 9353051 9501840 9155314 9493435 9501768 9503059 9494318 9502976 9495861 9459883 9486298 9008919 9488473 9499071 9416964 9451754 9393258 9479481 9463899 9496286 9497110 9494407 9383673 9485456

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membrane, are also thought to be associated with store operated/calcium release activated channels. In addition, La3+ and Gd3+ , which are non-selective cation channel blockers that inhibit the activity of many different cation channels, including TRPCs, also produced a marked inhibition of actin ring formation to a similar level to that of Ucn 1. However, modulators of other ion channel species previously shown to be associated with the mechanism of action of Ucn 1 in other tissues (e.g. nicardipine, which blocks Ltype Ca2+ channels, BayK8644 an L-type Ca2+ channel opener, and glibenclamide a KATP channel opener) had no effect on actin ring formation. TRPC channels are intimately associated with the regulation of Ca2+ concentrations within many cells and in particular, when associated with ORAI and STIM proteins. These produce functional store operated channels, which tightly control Ca2+ levels within intracellular compartments, in particular the endoplasmic reticulum. This is particularly important in Oc where Ca2+ handling is crucial for their proper functioning (Kajiya, 2012; Ong et al., 2013). As was found in chondrocytes, bone cells also contain members of the Ucn system. Ucn 1 mRNA was found to be expressed in Oc but not Ob. Oc was also shown to express the CRF-R2␤ receptor subtype (Combs et al., 2012), which is commonly found in peripheral tissues. In contrast, Ob expressed high levels of CRF-BP decoy receptor, whereas Oc do not, suggesting a possible autocrine/paracrine regulatory system for the Ucn 1 produced by Oc. These data suggest the possibility that Ucn 1 may essentially represent a selfregulator of Oc function, through an autocrine/paracrine effect on the Oc population. The concentration of Ucn 1 in the surrounding milieu could be tightly controlled by Ob derived CRF-BP to allow resorption when appropriate. This system has parallels with the well-established RANKL/Osteoprotegerin system in bone, since both systems employ a decoy receptor derived from Ob to terminate an Oc-targeted ligand signal (Martin, 2013). Importantly, however, the Ucn system demonstrates an alternative regulatory mechanism to that of the RANKL/OPG pathway for the inhibition of osteoclast differentiation and activity (Fig. 3).

4. Future perspectives for urocortin Because of the overwhelming amount of data that has been generated involving Ucn 1 within numerous disease conditions and to understand the wider role Ucn 1 plays in human disease, we conducted a novel bioinformatics analysis of this gene. We looked at the entire open access published literature in PubMed and PubMed Central. Using Biorelate’s bespoke DB service, we first found 1260 publications mentioning Ucn 1. Enrichment analysis of disease ontology and disease co-occurrences in these, revealed a disparate range of 147 significantly enriched disease concepts (p < 0.05), highlighting the broad influence of this protein in disease. Of these we find examples associated with stress which is the original role for Ucn1. We also find PD and inflammatory diseases. Interestingly, OP was not enriched (p = 0.21), perhaps reinforcing the lesser-known role of Ucn 1 in this disease (Table 1 and supplementery file 1). We next sought to characterise the molecular interactions involving Ucn 1, finding 52 unique genes/proteins directly or indirectly interacting with it (Table 2). From this table it is clear that Ucn 1 interacts with a remarkably diverse set of targets. Furthermore, analysis of these interactions confirms the disparate pathologies associate with Ucn 1. Probably the oldest and well known effect of Ucn 1 is on stress, by its actions on the hypothalamic/pituitary/adrenal -axis (HPA). It is noteworthy here that it has an effect on pro-opiomelanocortin (POMC) the large precursor polypeptide whose gene is expressed in both the anterior and intermediate lobes of the pituitary gland and encodes numerous hormones including the stress hormone, adrenocorticotropin (ACTH). This hormone is indeed regulated by the CRF family

Table 2 Ucn 1 molecular interactions. Interactions between proteins are defined by positive regulation, negative regulation, or binding. These were sourced through manual curation provided by Biorelate bespoke DB service of published peer-reviewed literature. Selected publications mentioning these interactions are included for reference. Interaction

Selected references

ANG positively regulates UCN UCN positively regulates ICAM1 UCN positively regulates LEP LEP positively regulates UCN UCN positively regulates STAR UCN positively regulates TH UCN negatively regulates AVP UCN positively regulates IL10 UCN positively regulates IL1B IL1B negatively regulates UCN UCN positively regulates IL4 UCN negatively regulates TNF

19318426, 2834258 19694731 11792665, 17952632, PMC2834774 11150641, 15228601 20171993 15911134, 15809070 9654364 19703147 11549672 19254747 1970314 19703147, 17947696, 17117478, 9814993, PMC3271957 PMC3362921, 16340217, 19318426 11549672, 16777977, 19211730, PMC3359671, PMC2834774 15784708 PMC2834774 19466989 PMC3362921, PMC3168230, 21476084, 16920976, PMC3082851 22306347, 19058138, 15664670, PMC2780655, 18670748 17154253 11208577 PMC3069736, 14563694 10199789, 12113883, 15804422, 9918231, 10341863 21289256, 16920724 PMC2834774, 19949969 14555790 16672665 PMC2780655, 21476084, 16368564, 8836534, 18234674 20171993 17131811 PMC3069736 19466989 14563694, 17885217 19211730, 19694731, 19211730 PMC3278674 PMC2773374, 16174714 11991736, PMC3069736 PMC3069736 12742625, 10650129 22244812 9753624 PMC3069736 PMC3069736 19694731 17952632 PMC3069736 17526650 15806110 PMC3069736 PMC3362921, PMC3168230, 21476084, PMC3181666, PMC3069736 16959871, 22306347, 15142984, 19058138, 14657255 PMC3069736 16933022 19694731, 19211730 PMC3069736 16672665 PMC3069736 9753624 16340217 PMC3069736 PMC3069736 11834446

TNF positively regulates UCN UCN positively regulates IL6 UCN positively regulates NOS3 TGFB1 negatively regulates UCN UCN negatively regulates TGFB1 Binding of UCN and CRHR2 UCN positively regulates CRHR2 Binding of UCN and NPY UCN negatively regulates NPY UCN negatively regulates PLA2G1B UCN positively regulates POMC UCN positively regulates PRL BMP2 negatively regulates UCN UCN positively regulates CTF1 ESR2 regulates UCN Binding of UCN and CRFBP UCN positively regulates CRHBP UCN negatively regulates PPP1R12A UCN regulates RAP1A UCN negatively regulates VEGFA UCN negatively regulates PLA2G6 UCN positively regulates NFKB1 Binding of UCN and CART UCN positively regulates MMP9 UCN positively regulates AKT UCN positively regulates KCNJ8 UCN positively regulates FOS UCN positively regulates MSTN UCN positively regulates NPPA UCN negatively regulates ANP UCN regulates RALGDS UCN positively regulates COX2 UCN positively regulates STAT3 UCN positively regulates DAB2IP UCN negatively regulates REN UCN positively regulates PKC UCN positively regulates NFE2L1 Binding of UCN and CRHR1 UCN positively regulates CRHR1 UCN regulates RND3 UCN negatively regulates MYL12B UCN positively regulates MAPK14 UCN positively regulates PRKAR1A ESR1 regulates UCN UCN positively regulates PRKCE UCN positively regulates Nppb IFNG positively regulates UCN UCN regulates GNB1 UCN regulates RAC2 UCN positively regulates HSP90AA1

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members including Ucn 1. Other important functions of Ucn 1 involve its role in cell survival, in particular apoptosis and protection against stressful stimuli. This is clearly seen in Table 2, where Ucn 1 has been found to interact with key regulators of apoptosis, including MAP Kinases, AKT, HSP90, and STAT3. Other important roles of Ucn 1 highlighted in Table 2 is on inflammation, where it has been shown to interact with numerous cytokines involved in the inflammatory response including IL10, IL6, IL1, IL-4, TGF␤ and TNF␣. There is also an important role for Ucn 1 in the cardiovascular system, where it has effects on vascular tone through Angiotensin II and NOS as well as pro-angiogenic effects through VEGF. Lastly, the role of Ucn1 in satiety and energy expenditure is becoming important. This is highlighted by its interaction with the central energy regulating adipokine leptin, which is released by adipocytes and activates leptin receptors in the arcuate nucleus of the hypothalamus resulting in the sensation of satiety. Of considerable interest here is the finding that leptin is responsible for the regulation of Ucn 1 expression in the brain and that the interaction of Ucn 1 and leptin is required for their efficient transport across blood brain barrier. Finally using David (Huang et al., 2009, supplementary file 2) we determined enriched genetically associated diseases with this gene list. The most enriched genetically associated diseases were bone density, preeclampsia, giant cell arthritis, and Q fever, among others. Significantly, that bone density disorders are the most enriched, perhaps highlights the role of Ucn 1 in OP, despite the lack of current research in this area.

5. Conclusion Ucn 1 is a key regulator of the organism’s overall response to stress and it is clear from this account that the involvement of Ucn 1 in health and disease is widening still further. It is now known to affect virtually every organ of complex mammalian systems. Understanding its mechanisms of action in these diverse cell types remains a challenge due to its pleiotropic actions and its promiscuity of receptor signalling pathways, which appears to be highly tissue specific. We feel that these difficult endeavours however, are both scientifically and clinically worthwhile, especially considering the evidence that Ucn 1 can mediate its effects after an insult has occurred. This suggests a putative role in restorative medicine and therefore, in some cases, could be given to patients as a treatment as well as a prophylactic. Furthermore, a deeper understanding of the diverse mechanisms of action of Ucn 1, may therefore give researchers new insights into the pathophysiology of many central and peripheral disorders and illuminate potential novel treatments for a variety of seemingly unrelated diseases. We feel that reviews of the future will need to be a combination of conventional data derived from peer reviewed publications and association studies which will produce tangential information. These will uncover deeper strata of information and therefore shed new light on novel, undetected associations and interactomes. The use of bioinformatics analysis here, has highlighted its value in uncovering further, novel understated areas of research.

Conflict of Interest The author declares no conflict of interest.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.biocel. 2014.12.005.

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Urocortin--from Parkinson's disease to the skeleton.

Urocortin (Ucn 1), a 40 amino acid long peptide related to corticotropin releasing factor (CRF) was discovered 19 years ago, based on its sequence hom...
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