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James E Galvin 《朊病毒》2011,5(1):16-21
Misfolded proteins are at the core of many neurodegenerative diseases, nearly all of them associated with cognitive impairment. For example, Creutzfeldt-Jacob disease is associated with aggregation of prion protein,1,2 Lewy body dementia and Parkinson disease with α-synuclein3,4 and forms of frontotemporal dementia with tau, TDP43 and a host of other proteins.5,6 Alzheimer disease (AD), the most common cause of dementia,7 and its prodromal syndrome mild cognitive impairment (MCI)8 are an increasing public health problem and a diagnostic challenge to many clinicians. AD is characterized pathologically by the accumulation of amyloid β-protein (Aβ)9,10 as senile plaques and in the walls of blood vessels as amyloid angiopathy.11,12 Additionally, there are accumulations of tau-protein as neurofibrillary tangles and dystrophic neurites.11,12 Biological markers of AD and MCI can serve as in vivo diagnostic indicators of underlying pathology, particularly when clinical symptoms are mild13–15 and are likely present years before the onset of clinical symptoms.16–19 Research to discover and refine fluid and imaging biomarkers of protein aggregation has undergone a rapid evolution20–22 and combined analysis of different modalities may further increase diagnostic sensitivity and specificity.23–26 Multi-center trials are now investigating whether imaging and/or cerebrospinal fluid (CSF) biomarker candidates can be used as outcome measures for use in phase III clinical trials for AD.27–29Key words: dementia, screening, biomarkers, amyloid, tau, Alzheimer disease, preclinical, presymptomaticCurrently, the diagnosis of AD is based on exclusion of other forms of impairment with definitive diagnosis requiring autopsy confirmation.30 Thus, there is a strong need to find easily measurable in vivo AD biomarkers that could facilitate early and accurate diagnosis31 as well as prognostic data to assist in monitoring therapeutic efficacy.32 Although biological markers such as MRI, PET scans and CSF increase the diagnostic likelihood that AD is present,9,18–20,33,34 biomarkers are invasive, uncomfortable, expensive and may not be readily available to rural areas, underserved communities, underinsured individuals or developing countries, making them impractical for broad use. However, the lessons learned from biomarkers can be applied to increase the likelihood that clinicians will be able to detect disease at earlier stages in the form of dementia screening.Public health may be best defined as the organized efforts of society to improve health, often framed in terms of primary, secondary and tertiary prevention. Prevention encompasses an understanding of causation, alteration of natural history of disease and understanding of pathophysiological mechanisms.35 The clearest application of this from a public health perspective is in the setting of secondary prevention (i.e., screening)—early detection as a core element, coupled with treatments or preventative actions to reduce the burden of disease.35 In this instance we seek to identify individuals in whom a disease has already begun and who may be experiencing very mild clinical symptoms but have not yet sought out medical care. The objective of effective screening is to detect the disease earlier than it would have been detected with usual care. Recent healthcare reform (Accountable Care Act)36 proposes a Personalized Prevention Plan including screening for cognitive disorders, reimbursable through Medicare. Thus tying knowledge about dementia screening with underlying biology of protein misfolding associated with neurodegenerative disease can have enormous implications.A review of the natural history of dementia illustrates this point (Fig. 1). The timeline of disease from presumptive start to the patient demise is plotted. Stage I marks the biologic onset of disease; however this point often cannot be identified and may begin years to decades before any evidence is apparent (represented by dashed lines). As this stage is subclinical, it is difficult to study in humans but lends itself nicely to animal models. At some point in the progression of the biology, stage II begins heralding the first pathologic evidence of disease could be obtained—in the case of AD this could include CSF measurements of amyloid and tau22,26,27 or PET imaging with amyloid ligands.18,37 Subsequently, the first signs and symptoms of disease develop (stage III). Till this point, the disease process has been entirely presymptomatic. Beginning with the onset of symptoms, the patient may seek medical care (stage IV) and eventually be diagnosed (stage V). From stage III onwards, the patient enters the symptomatic phase of disease. From this point, the patient is typically treated with various pharmacologic and nonpharmacologic approaches towards some outcome. Another way to envision the disease spectrum is from the biological onset to the seeking of medical attention as the preclinical phase of disease with the clinical phase beginning with the initial clinical investigations into the cause of the patients'' symptoms.Open in a separate windowFigure 1Model of the natural history of AD. Timeline from presumptive start of AD through patient diagnosis is plotted. The initiation of biological changes (stage I) marks the onset of disease and begins years to decades before any evidence is apparent (represented by dashed lines). At some point the first pathologic evidence of disease (stage II) begins and in theory can be detected with biomarkers such as CSF measurements of amyloid and tau or PET imaging with amyloid ligands. Subsequently, the first signs and symptoms of disease develop (stage III) followed by the patient seeking medical attention (stage IV) and finally a diagnosis is established (stage V). This timeline can be clustered into a presymptomatic phase (stages I–III) and a symptomatic phase (stages III–V). An alternative way to envision the disease spectrum is from the biological onset to the seeking of medical attention (stages I–IV) as the preclinical phase of disease with the clinical phase beginning with the initial clinical investigations into the cause of the patients'' symptoms (stages IV and V). Stage III is the ideal time for dementia screening.What is the value of thinking about disease in this fashion? Such models allow researchers and clinicians to model the approach to finding and applying new diagnostics and offering new interventions. From stage I to stage III, the patient is the presymptomatic, preclinical phase of disease. The only means of detection would be with a biological marker that reflected protein misfolding or some proxy marker of these events. Although longitudinal evidence of cognitive change exist from 1–3 years before clinical diagnosis, raw scores on neuropsychological testing during this time remains in the normal range.38 After stage IV, the patient is in the symptomatic, clinical phase of disease. Testing here is centered on confirming the suspected diagnosis, correctly staging the disease and initiating the appropriate therapies. Basic scientific approaches focusing on the presymptomatic, preclinical phase and clinical care approaches focusing on the symptomatic, clinical phase are well established and will continue to benefit from additional research.However, if we focus only on these two phases, an opportunity will be missed to make a decidedly important impact in the patient''s well-being. From stage III to stage IV, the patient enters symptomatic, preclinical phase of disease; symptomatic because the patient or family is beginning to detect some aspect of change, but preclinical because these signs and symptoms have not yet been brought to medical attention. In the case of AD (and the other forms of dementia) this period may go for an extended length of time as patients, families and clinicians dismiss early cognitive symptoms as part of the normal aging process. Thus, the rationale for screening is that if we can identify disease earlier in its natural history than would ordinarily occur, intervention measures (those currently available and those that are being developed) would be more effective. Dementia screening therefore would be best suited to detect cognitive impairment at the beginning of disease signs (stage III), particularly if these screening measures reflect what is known about the symptomatic, clinical phase of disease and correlate with the pathologic changes occurring in the brain during the pre-symptomatic, preclinical phase of disease.In a recent paper, we evaluated the relationship between several dementia screening tests and biomarkers of AD.40 We tested whether a reliable and validated informant-based dementia screening test (the AD8)41,42 correlates with changes in AD biomarkers and, if positive, screening with the AD8 clinically supports an AD clinical phenotype, superior to a commonly used performance-based screening tests including the Mini Mental State Exam (MMSE)43 and the Short Blessed Test (SBT).44 A total of 257 participants were evaluated, administered a comprehensive clinical and cognitive evaluation with the Clinical Dementia Rating scale (CDR)45 used as the gold standard. Participants consented to and completed a variety of biomarker studies including MRI, amyloid imaging using the Pittsburgh Compound B (PiB)37,46 and CSF studies of Aβ42, tau and phosphorylated tau at Serine 181 (p-tau181).23,24 The sample had a mean age of 75.4 ± 7.3 years with 15.1 ± 3.2 years of education. The sample was 88.7% Caucasian and 45.5% male with a mean MMSE score of 27.2 ± 3.6. The formal diagnoses of the sample was 156 CDR 0 cognitively normal, 23 CDR 0.5 MCI, 53 CDR 0.5 very mild AD and 25 CDR 1 mild AD. Participants with positive AD8 scores (graded as a score of 2 or greater) exhibited the typical AD fluid biomarker phenotype characterized by significantly lower mean levels of CSF Aβ42, greater CSF tau, p-tau181 and the tau(s)/Aβ42 ratios.26,27 They also exhibited smaller temporal lobe volumes and increased mean cortical binding potential (MCBP) for PiB imaging similar to studies of individuals with AD.18,19 These findings support that informant-based assessments may be superior to performance-based screening measures such as the MMSE or SBT in corresponding to underlying AD pathology, particularly at the earliest stages of decline. The use of a brief test such as the AD8 may improve strategies for detecting dementia in community settings where biomarkers may not be readily available and also may enrich clinical trial recruitment by increasing the likelihood that participants have underlying biomarker abnormalities.40To gain a better understanding of changes in biomarkers in the symptomatic, preclinical phase, a post hoc evaluation of the 156 individuals who were rated as CDR 0 no dementia at the time of their Gold Standard assessment was completed. Some of these nondemented individuals have abnormal AD biomarkers, but in the absence of performing lumbar punctures or PET scans, is it possible to detect evidence of change? AD8 scores for 132 individuals were less than 2; thus their screening test suggests no impairment (mean AD8 score = 0.30 ± 0.46). However 25 of these individuals had AD8 scores (≥2) suggesting impairment (mean AD8 score = 2.4 ± 0.91). Applying the model described in Figure 1, some of these individuals are hypothesized to be in the symptomatic, preclinical phase of disease. No difference in age, education, gender or brief performance tests (MMSE or SBT) were detected between groups (45 is increased in the individuals with higher AD8 scores supporting that informants were noticing and reporting changes in the participants cognitive function. A review of the individual AD8 questions that were first reported to change suggest that informants endorsement of subtle changes in memory (repeats questions, forgets appointments) and executive ability (trouble with judgment, appliances, finances) are valuable early signs. This is consistent with previous reports that changes in memory and judgment/problem solving CDR boxscores in nondemented individuals correlate with findings of AD pathology at autopsy.17 Although biomarkers do not reach significance in this small sample, the direction of change in favor of “Alzheimerization” of this group suggests that some of these individuals may be in the symptomatic, preclinical phase of disease. More research with larger sample sizes and longitudinal follow-up is needed to confirm this hypothesis. It should be also noted that not all individuals with an AD8 score of 2 or greater have AD. The AD8 was designed to detect cognitive impairment from all causes, and as such, these mildly affected individuals may have other causes for their cognitive change such as depression, Lewy body dementia or vascular cognitive impairment.41,42
Open in a separate windowApoE, apolipoprotein E; CDR, Clinical Dementia Rating; MMSE, Mini Mental State Exam; SBT, Short Blessed Test; MCBp, mean cortical binding potential; CSF, cerebrospinal fluidTo explore this further, changes in AD biomarkers (CSF Aβ42, Tau and PiB-PET) were plotted against the age of the participant (Fig. 2). Previous research suggest that biomarker changes are more commonly seen in older populations47 and increasing age is the greatest risk factor for developing AD.7 AD8 scores of 0 or 1 (no impairment) are depicted as filled circles while AD8 scores of 2 or greater (impairment) are depicted as open squares. Regression lines are plotted for the entire cohort (dashed black line) and for each subset (black for AD8 no impairment; gray for AD8 Impairment). The top row (Parts A–C) represents biomarker profiles for the entire sample of 257 individuals divided by their AD8 scores. With age, there are changes in biomarkers with decreasing CSF Aβ42 (A), increasing CSF Tau (B) and increased PiB-PET binding potential (C). The effect of age on CSF biomarkers is most marked in the AD8 No Impairment group (black line) while changes in PiB binding is seen only in the AD8 Impaired group (gray line). The second row in Figure 2 (Parts D–F) represents biomarker profiles for the 156 individuals who were rated as CDR 0 no dementia at the time of their Gold Standard, 25 of whom had AD8 scores in the impaired range. Some of these individuals are hypothesized to be in the symptomatic, preclinical phase of AD. Similar age-related changes in CSF Aβ42 and PiB binding are seen with CSF Aβ42 having the greatest rate of decline in the AD8 no impairment group and PiB binding having the greatest rate of change in the AD8 impairment group. Increases in CSF Tau are seen as a function of age regardless of group.Open in a separate windowFigure 2Changes in AD biomarkers by age and AD8 scores. AD biomarkers are plots as a function of age (x-axis) and AD8 scores. AD8 scores of 0 or 1 (no impairment) are depicted as filled circles while AD8 scores of 2 or greater (impairment) are depicted as open squares. Regression lines are plotted for the entire cohort (dashed black line) and for each subset (black for AD8 no impairment; gray for AD8 impairment). The top row (A–C) represents biomarker profiles for the entire cohort (n = 257) divided by their AD8 scores. With age, there are changes in biomarkers with decreasing CSF Aβ42 (A), increasing CSF Tau (B) and increased PiB-PET binding potential (C). The effect of age on CSF biomarkers is most marked in the AD8 no impairment group (black line) while changes in PiB binding is seen only in the AD8 impaired group (gray line). The bottom row (D–F) represents biomarker profiles for the individuals rated CDR 0 no dementia (n = 156), 25 of whom had AD8 scores in the impaired range. Similar age-related changes in CSF Aβ42 and PiB binding are seen with CSF Aβ42 having the greatest rate of decline in the AD8 no impairment group and PiB binding having the greatest rate of change in the AD8 impairment group. Increases in CSF Tau are seen as a function of age regardless of group.While a number of interpretations are possible from this type of data, if one considers the model of disease in Figure 1 it appears that CSF changes in Aβ42 and Tau precede PiB binding changes in the presymptomatic, preclinical phase of disease consistent with previous attempts at modeling AD.25 Even with sensitive measurements, this phase is unlikely to be detected without some biological evaluation. At the start of the symptomatic, preclinical phase of AD, PiB binding increases and this may be detected by careful evaluation of the patient and a knowledgeable informant with a validated dementia screening instrument such as the AD8. As patients move into the symptomatic, clinical phase of disease, biomarkers are markedly abnormal as is most cognitive testing permitting careful staging and prognostication.AD and related disorders will become a public health crisis and a severe burden on Medicare in the next two decades unless actions are taken to (1) develop disease modifying medications,48 (2) provide clinicians with valid and reliable measures to detect disease at the earliest possible stage and (3) reimburse clinicians for their time to do so. While this perspective does not address development of new therapeutics, it should be clear that regardless of what healthcare reform in the US eventually looks like,1 dementia screening is a viable means to detect early disease as it enters its symptomatic phase. Dementia screening with the AD8 offers the additional benefit of corresponding highly with underlying disease biology of AD that includes alteration of protein conformation, protein misfolding and eventual aggregation of these misfolded proteins as plaques and tangles. 相似文献
Table 1
Characteristics of nondemented CDR 0 individuals stratified by AD8 scoresVariable | AD8 <2 | AD8 ≥2 | p value |
Clinical Characteristics | |||
Age, y | 75.2 (7.1) | 76.5 (8.4) | 0.41 |
Education, y | 15.4 (3.2) | 15.9 (2.7) | 0.47 |
Gender, % Men | 42.1 | 36.4 | 0.45 |
ApoE status, % at least 1 e4 allele | 25.8 | 34.4 | 0.08 |
Dementia Ratings | |||
CDR sum boxes | 0.04 (0.13) | 0.12 (0.22) | 0.01 |
MMSE | 28.6 (1.5) | 29.2 (1.1) | 0.07 |
SBT | 2.4 (3.1) | 2.3 (2.9) | 0.82 |
AD8 Questions Endorsed “Yes,” % | |||
Problems with judgment | 12.9 | 72.0 | <0.001 |
Reduced interest | 0 | 4.0 | 0.02 |
Repeats | 8.3 | 40.0 | <0.001 |
Trouble with appliances | 1.5 | 40.0 | <0.001 |
Forgets month/year | 0.8 | 0 | 0.66 |
Trouble with finances | 0.8 | 16.0 | 0.002 |
Forgets appointments | 2.3 | 28.0 | <0.001 |
Daily problems with memory | 20.0 | 66.7 | 0.008 |
Biomarkers | |||
MCBP, units | 0.12 (0.23) | 0.26 (0.39) | 0.06 |
CSF Aβ42, pg/ml | 596.7 (267.9) | 591.9 (249.9) | 0.95 |
CSF tau, pg/ml | 300.3 (171.5) | 316.7 (155.0) | 0.76 |
CSF p-tau181, pg/ml | 51.9 (24.0) | 56.9 (22.6) | 0.49 |
7.
Interactions between endothelial cells and the surrounding extracellular matrix are continuously adapted during angiogenesis, from early sprouting through to lumen formation and vessel maturation. Regulated control of these interactions is crucial to sustain normal responses in this rapidly changing environment, and dysfunctional endothelial cell behaviour results in angiogenic disorders. The proteoglycan decorin, an extracellular matrix component, is upregulated during angiogenesis. While it was shown previously that the absence of decorin leads to dysregulated angiogenesis in vivo, the molecular mechanisms were not clear. These abnormal endothelial cell responses have been attributed to indirect effects of decorin; however, our recent data provides evidence that decorin directly regulates endothelial cell-matrix interactions. This data will be discussed in conjunction with findings from previous studies, to better understand the role of this proteoglycan in angiogenesis.Key words: decorin, angiogenesis, motility, α2β1 integrin, insulin-like growth factor I receptor, Rac GTPaseLed by appropriate cues, the vascular system undergoes postnatal remodelling (angiogenesis), to maintain tissue homeostasis. Thus while much of the mature endothelium is quiescent, locally activated endothelial cells re-enter the cell cycle, and assume a motile phenotype essential for sprouting and neo-vessel formation. Concomitantly, the surrounding extracellular matrix (ECM) is significantly altered through de novo protein expression, deposition of plasma components and protease-mediated degradation. The latter liberates cryptic binding sites and sequestered growth factors in addition to intact and degraded ECM components, which themselves possess pro- and anti-angiogenic signalling properties. For supported blood flow, endothelium quiescence and integrity is re-established, and the ECM is organized into mature, cross-linked networks. In short, endothelial cells regulate ECM synthesis, assembly and turnover while the structure and composition of ECM in turn influences cellular phenotype. The ECM therefore, plays a critical role in control of endothelial cell behaviour during angiogenesis.Decorin is a member of the small leucine-rich repeat proteoglycan (SLRP) family, which was first discovered ‘decorating’ collagen I fibrils and was subsequently shown to regulate fibrillogenesis.1,2 Both the protein core and the single, covalently attached glycosaminoglycan (GAG) moieties of decorin are involved in this function, the relevance of which is demonstrated by the phenotype of the decorin null mouse, which exhibits loose, fragile skin due to dysregulated fibrillogenesis.2 Interestingly, a role for decorin in postnatal angiogenesis was also revealed by studies in the decorin null background. Corneal neoangiogenesis was reduced.3 Conversely, neo-angiogenesis was enhanced during dermal wound healing, although surprisingly this led to delayed wound closure.4 In this case, skin fragility due to the absence of decorin may have hindered wound closure, despite an increased blood supply. It is apparent however, that decorin plays a role in inflammation-associated angiogenesis. Indeed, endothelial cells undergoing angiogenic morphogenesis in this environment express decorin, while quiescent endothelial cells do not,3–6 indicating that decorin modulates endothelial cell behaviour specifically during inflammatory-associated remodelling of the vascular system.To understand decorin effects on angiogenic morphogenesis within a minimalist environment, various in vitro models of angiogenesis have been employed (6 Similarly, decorin expression enhanced tube formation on matrigel,8 but in other studies utilising this substrate was found to either have no influence9 or to inhibit tubulogenesis induced by growth factors.10 In yet another study, decorin inhibited tube formation when presented as a substrate prior to addition of collagen I.7 These contrasting observations may reflect the importance of the micro-environment within which decorin is presented. Alternatively, controversial results could result from different sources of decorin since cell types differ in their post-translational modifications of the GAG moiety. Hence, varying length or sulfation patterns of GAG chains may account for different biological activities of decorin. Discrepancies can also be explained as artefacts due to different purification protocols, such as when denaturing conditions are used to extract decorin from tissue. Taken together however, these observations suggest that decorin is neither a pro- nor an anti-angiogenic factor per se, but rather a regulator of angiogenesis, dependent on local cues for different activities. Further, that decorin is capable of both enhancing and inhibiting tubulogenesis may suggest a role in balancing vessel regression versus persistence. Immature vessels have a period of plasticity prior to maturation, during which they can be remodelled, and either regress, or given the appropriate signals, proceed to maturity.11 As a modulator of tube formation, it is tempting to speculate that decorin could influence the switch from immature to mature vessels, favouring one or the other in conjunction with signals from the local environment.
Open in a separate windowDecorin has been demonstrated to influence cell adhesion and motility, in particular, its influence on endothelial cell adhesion, migration and tube formation is controversial, and is the main focus of this table. Some additional key effects of decorin on fibroblast and platelet adhesion and motility are also summarised. In each case, the extracellular matrix environment in which the assay was conducted is shown, and where known, the proposed mechanism is stated.What are the molecular mechanisms by which decorin influences tubulogenesis? Since endothelial cell-matrix interactions control all aspects of angiogenesis, from motility, sprouting and lumen formation, to survival and proliferation, the role of decorin should be considered in this regard. Indirectly, decorin could quite feasibly modulate cell-matrix interactions through regulation of matrix structure and organisation2,12 and growth factor activity.13 However in vitro studies have begun to unravel rather more direct mechanisms. Studies on fibroblasts indicate that decorin can inhibit cell-matrix interactions by binding to and masking integrin attachment sites in matrix substrates. For instance, decorin inhibits fibroblast adhesion by competing with cell-surface GAG-containing CD44 for GAG binding sites on collagen XIV;14 similarly, decorin inhibits fibroblast adhesion to thrombospondin by interacting with the cell-binding domain of this substrate15 and may compete with fibroblast cell-surface heparin sulphate proteoglycans for binding to fibronectin.16 While such studies are rather lacking in endothelial cell systems, any one of these interactions could be relevant to endothelial cells. However, that decorin slightly enhanced endothelial cell attachment to fibronectin and collagen I in our system points to the existence of alternative mechanisms.17Indeed, a recent study demonstrated that decorin is an important signalling molecule in endothelial cells, where it both signals through the insulin-like growth factor I receptor (IGF-IR) and competes with the natural ligand for interaction.18 Further, decorin appears to be biologically available and relevant for interaction with this receptor in vivo. Increased receptor expression was observed in both native and neo-vessels in decorin knockout mouse cornea in conjunction with reduced neoangiogenesis. In accordance with this, decorin downregulates the IGF-IR in vitro,18 indicating that signalling through, and control of IGF-IR levels by decorin could be an important factor in regulating angiogenesis. Additionally, immobilised decorin supports platelet adhesion through interactions with the collagen I-binding integrin, α2β1.19 We have shown that decorin—α2β1 integrin interaction may play a part in modulating endothelial cell—collagen I interactions, and further, have demonstrated that decorin promotes motility in this context through activation of IGF-IR and the small Rho GTPase, Rac.17 Similarly, decorin stimulates fibroblast motility through activation of small Rho GTPases,20 supporting a direct mechanism by which decorin influences cell-matrix interactions and motility, via activation of key regulators of cytoskeleton and focal adhesion dynamics. It should also be noted that signalling by decorin directly through ErbB receptors has also been extensively demonstrated in cancer cell systems where these receptors are frequently overexpressed.21 This interaction was not relevant to human umbilical vein endothelial cells18 although a recent study found that decorin activated the epidermal growth factor receptor in mouse cerebral endothelial cells.8 These differences presumably depend on cell-specific factors such as receptor availability as well as relative receptor affinities. In a complex system such as angiogenesis, multiple mechanisms doubtlessly are involved. However, it is clear that modulation of cell-matrix interactions by decorin could certainly be expected to play a key role in contributing to regulation of postnatal angiogenesis.Signals from the extracellular matrix via integrins and from growth factors to their receptors are co-ordinately integrated into the complex angiogenic cascade. Evidence exists to suggest that decorin could regulate cell-matrix interactions during early tube formation, i.e., endothelial cell sprouting and cell alignment, through both influencing integrin activity and signalling through IGF-IR.17 Later stages of angiogenesis, such as lumen formation and maturation are also potentially regulated by decorin through activation of Rac and α2β1 integrin,17 since activity of both these molecules is integral to this phase of angiogenesis.22 Additionally, Rac activity is implicated in regulating endothelium permeability and integrity,23 providing further possibilities in control of endothelium function by decorin. Further investigations would be required however, to establish whether decorin exerts its effects on tubulogenesis through these molecular mechanisms.Of relevance to α2β1 integrin-dependent endothelial cell interaction with collagen I, sprouting endothelial cells would encounter interstitial ECM, of which collagen I is a major component. Further, a ‘provisional’ matrix containing collagen I is secreted by sprouting endothelial cells and may be required for motility,24 and tube formation.25 Theoretically, various interactions could exist between decorin, collagen type I and α2β1 integrin in this context, which may be differentially supported through various stages of angiogenesis. Up to eleven interaction sites of α2β1 integrin have been postulated to exist within collagen I, albeit with different affinities towards this receptor. Some of these binding sites may only be recognized by the integrin in its highly active conformation.26 By influencing the collagen I binding activity of α2β117 decorin could thus alter the number of endothelial cell—collagen I contacts, thereby modulating adhesion and motility. Additionally, some decorin and α2β1 integrin binding sites may overlap, or are in close proximity.27 By virtue of this location, decorin would be ideally placed to locally modulate collagen I—binding activity of the integrin. Interestingly, modulation of activity of both α2β1 integrin and the small Rho GTPase Rac by decorin also could have implications for collagen I fibrillogenesis, which in turn, would indirectly influence cell-matrix interactions. Both the related Rho GTPase RhoA, and α2β1 integrin are involved in cellular control of pericellular collagen I fibrillogenesis.28 Thus in addition to regulating cell independent fibrillogenesis1 decorin could potentially influence cell-mediated aspects of this process. Pertinent questions remain therefore, as to under which biological situations is the interaction between α2β1 integrin and decorin relevant, and does decorin influence α2β1 integrin activity on the cell-surface through direct interactions, and/or by inside-out signalling through the IGF-I receptor (or alternative receptors)? Further, how do differential decorin/α2β1 integrin/collagen I interactions mediate fibrillogenesis and cell-matrix interactions?Interaction of decorin with multiple binding partners makes it challenging to fully understand the role of decorin in angiogenesis (Fig. 1). A consideration of the relative accessibility and affinity of binding sites on both decorin and its'' binding partners would facilitate further understanding. It is still an open question whether collagen I—bound decorin can simultaneously interact with other ligands. In the case of the IGF-IR, the binding site on the concave surface of decorin overlaps with that of collagen I, thus mutually exclusive interactions seem more likely. That decorin clearly influences both collagen I matrix integrity and IGF-IR activity in vivo, would suggest that decorin is not exclusively associated with collagen I. Perhaps decorin occurs in a more ‘soluble’ form when locally secreted by endothelial cells undergoing angiogenic morphogenesis. Does collagen-bound decorin interact simultaneously with α2β1 integrin? This could be a possibility, since decorin core protein interacts with collagen I, allowing the possibility of GAG—integrin interaction. In this scenario however, interaction of α2β1 integrin with the GAG moiety of decorin in preference to collagen I might sound improbable. Nevertheless, during remodelling, interactions such as these could occur in a transient manner, and be crucial in controlling cell-matrix interactions in a rapidly changing environment. Interestingly, decorin interacts with IGF-IR via the core protein,18 and with α2β1 integrin via the GAG moiety17 raising yet another possibility of simultaneous decorin interaction with multiple binding partners. Additionally, while it is a matter of some debate whether decorin exists predominantly as a monomer or as a dimer in a physiologically relevant environment, it has been proposed that collagen-bound decorin could support simultaneous interactions of decorin with additional binding partners, and that dimer-monomer transitions also could facilitate differential interactions.29 Perhaps supporting multiple simultaneous interactions of decorin, the phenotype of patients with a progeroid variant of Ehlers-Danlos Syndrome indicates an essential role for properly glycosylated decorin (and the related SLRP biglycan). These patients exhibit skeletal and craniofacial abnormalities, loose skin and deficiencies in wound healing as a direct result of abnormal decorin and biglycan glycosylation, such that approximately half the population of decorin is secreted as the core protein only.30 Notably, the defect in loose skin and in wound healing is similar to the phenotype of the decorin knockout mouse.2,4 Evidently, the core protein alone cannot maintain normal function in vivo, despite being responsible for several important interactions of decorin, in particular, binding to collagen I and the IGF-IR. These studies may therefore support a requirement for simultaneous interactions of the core protein and GAG moieties for proper function of decorin.Open in a separate windowFigure 1Decorin influences cell-matrix interactions through multiple mechanisms. Decorin signals through the IGF-IR via the core protein moiety (grey diamond), and may simultaneously interact with the α2 subunit (cross-hatched subunit) of α2β1 integrin via the GAG moiety (wavy black line) (A). Activation of Rac through IGF-IR enhances motility by modulating cytoskeleton dynamics and may influence α2β1 integrin activity for collagen I through inside-out signalling (B). Decorin induces large, peripheral vinculin (grey oval)-positive focal adhesions by signalling through IGF-IR and/or α2β1 integrin (C and D). Decorin could also directly influence α2β1 integrin activity through binding to the α2 subunit and/or simultaneous interactions with collagen I (thick wavy black line) through the core protein. Collagen I interacts with the A-domain (white circle) of the α2 subunit at a site distinct to that of decorin (D). In summary, activation of IGF-IR, Rac and modulation of α2β1 integrin affinity for collagen I by decorin modulates cell-matrix interactions and contributes to enhanced motility and tubulogenesis in a collagen I environment.Modulation of cell-matrix interactions by decorin plays a key role in modulating endothelial cell motility and angiogenesis in vivo, and some of the mechanisms responsible have been elucidated in conjunction with in vitro studies. The large number of potential interactions of decorin with multiple matrix components and cell-surface receptors makes a clear understanding difficult. However, direct activation of signalling pathways by decorin has been highlighted recently as likely to play an important role. In conclusion, a better understanding of the mechanisms by which decorin regulates vessel formation and persistence would contribute to understanding how angiogenesis is dysregulated in a clinical setting, and how rational therapeutic strategies can be developed to restore tissue function and homeostasis. 相似文献
Table 1
Summary of the key functions of decorin in controlling cell behaviourCell type | Function | Decorin addition | Environment/Mechanism | References |
Endothelial (HUVEC derived) | Enhanced tubulogenesis | Overexpression | Collagen I lattices, enhanced survival potentially IGF-IR mediated | 6, 18 |
Mouse cerebral endothelial cells | Enhanced tubulogenesis | Overexpression | Matrigel substrate, EGFR activation leads to VEGF upregulation | 8 |
HUVEC | No effect on tubulogenesis | Exogenous | Matrigel substrate | 9 |
HUVEC | Inhibited tubulogenesis | Exogenous | Matrigel substrate, growth factor induced | 10 |
HUVEC, HDMEC | Inhibited tubulogenesis | Substrate | Collagen I lattice overlay | 7 |
HUVEC | Minimal adhesion | Substrate | Decorin substrate | 7 |
HUVEC | Inhibited adhesion | Exogenous | Collagen I and fibronectin | 10 |
HUVEC | Inhibited migration | Exogenous | VEGF-mediated chemotaxis through gelatin | 10 |
Endothelial (HUVEC derived) | Enhanced adhesion | Exogenous | Collagen I, fibronectin | 17 |
BAE | Inhibited migration | Overexpression | Collagen I, enhanced fibronectin fibrilllogenesis by decorin | 12 |
Endothelial (HUVEC derived) | Enhanced motility | Exogenous | Collagen I, Decorin activates IGF-IR/Rac-1 and α2β1 integrin activity | 17 |
Human lung fibroblast | Enhanced motility | Exogenous | Decorin activates Rho GTPases, mediators of motility | 20 |
Human foreskin fibroblast | Inhibited adhesion | Exogenous | Decorin GAG moiety competes with CD44 for binding to collagen XIV | 14 |
Mouse Fibroblast (3T3) | Inhibited adhesion | Exogenous | Decorin competes with cells for interaction with thrombospondin at the cell-binding domain | 15 |
Human fibroblast | Inhibits adhesion | Exogenous | Decorin GAG competes with cell-surface heparin-sulphate for interaction with fibronectin | 16 |
Platelets | Supported adhesion | Substrate | Decorin interacts with, and signals through α2β1 integrin on platelets | 19 |
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9.
Nicholas Holton Kate Harrison Takao Yokota Gerard J Bishop 《Plant signaling & behavior》2008,3(1):54-55
Brassinosteroids (BRs) are perceived by Brassinosteroid Insensitive 1 (BRI1), that encodes a leucine-rich repeat receptor kinase. Tomato BRI1 has previously been implicated in both systemin and BR signalling. The role of tomato BRI1 in BR signalling was confirmed, however it was found not to be essential for systemin/wound signalling. Tomato roots were shown to respond to systemin but this response varied according to the species and growth conditions. Overall the data indicates that mutants defective in tomato BRI1 are not defective in systemin-induced wound signalling and that systemin perception can occur via a non-BRI1 mechanism.Key words: tomato BRI1, brassinosteroids, systemin, wound signallingBrassinosteroids (BRs) are steroid hormones that are essential for normal plant growth. The most important BR receptor in Arabidopsis is BRASSINOSTERIOD INSENSITIVE 1 (BRI1), a serine/threonine kinase with a predicted extracellular domain of ∼24 leucine-rich repeats (LRRs).1,2 BRs bind to BRI1 via a steroid-binding domain that includes LRR 21 and a so-called “island” domain.2,3 In tomato a BRI1 orthologue has been identified that when mutated, as in the curl3 (cu3) mutation, results in BR-insensitive dwarf plants.4 Tomato BRI1 has also been purified as a systemin-binding protein.5 Systemin is an eighteen amino acid peptide, which is produced by post-translational cleavage of prosystemin. Systemin has been implicated in wound signalling and is able to induce the production of jasmonate, protease inhibitors (PIN) and rapid alkalinization of cell suspensions (reviewed in ref. 6).To clarify whether tomato BRI1 was indeed a dual receptor it was important to first confirm its role in BR signalling. Initially this was carried out by genetic complementation of the cu3 mutant phenotype.7 Overexpression of tomato BRI1 restored the dwarf phenotype and BR sensitivity and normalized BR levels (35S:TomatoBRI1 complemented line Wt* cu3* 6-deoxocathasterone 566 964 676 6-deoxoteasterone nd 47 48 3-dehydro-6-deoxoteasterone 87 62 69 6-deoxotyphasterol nd 588 422 6-deoxocastasterone 1,755 6,247 26,210 castasterone 255 637 17,428 brassinolide nd nd nd