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 Table of Contents  
Year : 2017  |  Volume : 3  |  Issue : 1  |  Page : 132-140

Part 2: The extracellular matrix in undiagnosed connective tissue disease

1 Department of Internal Medicine, Lewis Katz School of Medicine, Pennsylvania 18015, USA
2 Department of Anesthesiology, University of Pennsylvania, Pennsylvania 18015, USA
3 Department of Medicine, Lardy Hardinge Medical College, New Delhi, India
4 Department of Pathology, St. Luke's University Health Network, 801, Ostrum Street, Bethlehem, Pennsylvania 18015, USA
5 Department of Internal Medicine, St. Luke's University Health Network, 801, Ostrum Street, Bethlehem, Pennsylvania 18015, USA

Date of Web Publication7-Jul-2017

Correspondence Address:
Sudip Nanda
Department of Internal Medicine, St. Luke's University Hospital Network, 801, Ostrum Street, Bethlehem, Pennsylvania 18015
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2455-5568.209846

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Connective tissue (CT) is essential for maintaining the functional integrity of the human body. Diseases due to CT malfunction are usually associated with deregulation at the molecular level, corresponding to essential components of the extracellular matrix (ECM). While many conditions have been identified and categorized, the complexity of the ECM yields many yet unclassified possibilities that could manifest as systemic disease. In this paper, we highlight a patient's presentation with systemic disease as a means to explore possible, unclassified ECM aberrations that hold promise as ubiquitous CT disruptors.
The following core competencies are addressed in this article: Patient care, Medical knowledge.

Keywords: Extracellular matrix, fibroblasts, fibulin, proteoglycans, transforming growth factor-beta

How to cite this article:
Stone LE, Fegley MW, Pangtey G, Longo S, Nanda S. Part 2: The extracellular matrix in undiagnosed connective tissue disease. Int J Acad Med 2017;3:132-40

How to cite this URL:
Stone LE, Fegley MW, Pangtey G, Longo S, Nanda S. Part 2: The extracellular matrix in undiagnosed connective tissue disease. Int J Acad Med [serial online] 2017 [cited 2022 Jan 25];3:132-40. Available from: https://www.ijam-web.org/text.asp?2017/3/1/132/209846

  Introduction Top

Connective tissue (CT) diseases are often challenging to diagnose due to their widespread and seemingly disconnected symptoms. Indeed, well-known CT diseases, such as Ehlers–Danlos and Marfan syndrome (MF) are marked by systemic abnormalities, ranging from vascular to skeletal manifestations.[1] We propose that given the patient's constellation of symptoms, he possesses a pathological, uncategorized CT dysfunction. Although extensive genetic testing for common CT conditions yielded no positive results, we are compelled to look deeper into the regulation of CT development and maintenance as a source of his symptoms to deduce a molecular cause for his condition. We begin with a brief discussion of typical connective disease symptoms, followed by a discussion of the structure of the extracellular matrix (ECM) and a discourse on the relevant pathways for ECM maintenance that could be aberrant in this patient.

  Case Report Top

The patient is a 26-year-old male presenting to the clinic with systemic complaints. His medical history indicates a history of vertebral artery aneurysm at age 14 as well as a splenic artery aneurysm, celiac axis aneurysm, and splenectomy at age 21. He has sustained numerous pneumothoraxes and demonstrations of reduced gastrointestinal integrity, including two  Mallory-Weiss tear More Detailss at age 22, Dieulafoy's lesion, and multiple intestinal bleeds. In addition, the patient has multiple café-au-lait macules on his skin, a high arched palate, and a marked pectus excavatum, among others. Genetic testing revealed nonmutated Collagen I and III, Fibrillin I, and transforming growth factor-beta receptors 1 and 2 genes, associated with Ehlers–Danlos vascular type, Marfan syndrome, and Loeys–Dietz syndrome, respectively. No definitive diagnosis of his condition has been identified.

  Discussion Top

Common connective tissue disease manifestations

Due to the marked presentations of CT diseases, there is no single epidemiological value quantifying CT disease incidence.[2] Thus, we will conduct our discussion with a brief overview of three well-known CT diseases – Marfan syndrome, Ehlers–Danlos, and Loeys–Dietz syndrome (LDS). For a comparison between the patient's symptoms and these three conditions, refer to table [Table 1][6],[7],[8],[9],[10],[11].
Table 1: Patient's symptoms compared to three notable connective tissue conditions

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Marfan syndrome is estimated to appear in 1:5000 of the population. While there are many subtypes of this condition, the most notable is caused by a mutation in the gene for fibrillin 1, whose significance will be discussed later. The most visually striking features of this condition are patient's elongated limbs and pectus excavatum. Other manifestations tend to be variable, although the most worrisome include weakened muscular arteries and susceptibility for pneumothorax.[3]

Similar to Marfan syndrome, Ehlers–Danlos is estimated to appear in 1:5000 individuals. Although there are six identified categories of Ehlers–Danlos, the most common is linked to a mutated COL5A gene encoding for a collagen subunit (discussed later). However, unlike MF, symptom presentation varies considerably by disease subtype, including the joint hyper-flexibility and poor wound healing of the classical type and hollow organ rupture, aneurysm, and skeletal abnormalities of the vascular type.[4]

LDS is commonly linked to a polymorphism in either transforming growth factor beta receptor 1 (TGFBR1) or TGFBR2. The classification of this condition is relatively new, thus no rigorous study has yet presented a population-wide incidence report. Patients with this condition are typically at high risk of an arterial aneurysm and tortuosity, skeletal abnormalities, and wound healing defects.[5]

While certainly not a comprehensive analysis of these three conditions, this limited overview yields a number of key patterns necessary for our future discussion. First, we see that CT disease is not multifactorial but often caused by a single, isolated genetic mutation. We also note that these single polymorphisms are pleiotropic, affecting seemingly disconnected organ systems. While it is possible that the patient's symptoms are the result of a number of aberrations, parsimony dictates that we first attempt to identify a common thread among his symptoms. Second, we note that even though the known CT diseases are associated with different polymorphisms, their symptomology is relatively overlapping. Thus, we can imply that there seems to be a pattern of common CT disease symptoms, differentiated by nuance and severity. In the case of our patient, we note a number of the common symptoms present in his history [Table 1].

Organization of the extracellular matrix

To better understand the pathology of CT disease, it is necessary to discuss the basic organization of CT. This process necessarily requires us to narrow our scope of focus due to the ubiquitous function and presence of CT in the body. Indeed, CT is laid down throughout embryological development and continually remodeled throughout the lifetime. It encompasses a number of sub-classifications, including adipose, blood, and bone, to name a few.[12] The scope of this paper will address general CT components present in multiple organ systems with the expectation that an abnormality in any one of them can manifest as a multisystem disorder. The key players in connective tissue - in particular, the ECM - offer an opportunity for exploration into CT pathology, as many ECM components are indicted in known CT conditions.[1] For a comprehensive list of ECM components beyond our focused discussion, see [Table 2][13],[14],[15],[16],[17],[18],[19] and [Figure 1].
Table 2: Components of the extracellular matrix

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Figure 1: Overview of extracellular matrix structure and suggested pathogenesis

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Collagen and elastin

The ECM can be viewed as a layered stack of fibers and networking molecules forming a sheath-like structure around other tissues types, such as epithelium.[1] In this structural format, the ECM “connects” one tissue [20] type to the next, therefore serving as a supportive bridge between the tissues. This structure also creates a sort of sieve-like filter between tissue types, regulating molecular and cellular traffic between tissues. The many interconnected fibrous components present are synthesized by fibroblasts, resident cells of the ECM.[12] Collagen is considered the primary structural scaffolding protein, although some forms, such as Type X, are exclusively networkers. Once the subunits are synthesized in their pre-pro-form, they are excreted from their maker fibroblasts as pre-pro-collagen to be processed and bundled extracellularly into fibers.

Elastin, too, is produced by fibroblasts. As with collagen, elastin must also undergo processing to form elastic fiber aggregates, yielding stretch, and resilience to the ECM.[1] The finalized product is a central core of elastin surrounded by glycoproteins, fibrillin, and other proteins. Elastic fibers are a significant component of arterial media and also widely distributed throughout lungs, ligaments and tendons, vascular tissue. Elastic fibers also regulate the activity of TGF-beta through interaction with fibrillin.


Once the collagens and elastins are produced, they are linked together into the scaffold structure by a number of networking molecules. These molecules serve to anchor fibers to the plasma membrane of a nearby tissue, ensuring tight ECM-tissue coupling. The first of these networkers worthy of attention is fibronectin, often considered the key “matrix organizer,” who, among other things, connects collagens to integrins embedded in the tissue cell surface.[22] The second is laminin, which is located in the basement membrane. It interacts with collagen VI, integrins, and dystroglycans, enhancing the formation of a stable matrix.[12] Fibrinogen is another glycoprotein that binds to a variety of proteins including fibronectin, albumin, von Willebrand factor, thrombospondin, interleukin one, and many others.

Some components of the ECM can also be classified as ECM modifiers. Notables among this category include fibulins, who stabilize cross-linked elastin strands into fibers, and fibrillins, whose regulating presence ensures the integrity of elastin fiber production. Fibrillin mutations are notorious as the causative aberration in Marfan's syndrome.[12] However, fibrillins also play a role in critical signaling pathways. It is known that the TGF-beta family, who plays a role in signaling ECM deposition, is regulated by fibrillin-1.[23]

A discussion of modifiers must also include the tenascin family. Tenascin-R is found in the central nervous system, tenascin-X and Y in skeletal and CT, and tenascin-C and W in developing tissue. Tenascin-X members regulate collagen deposition and elastin formation. The crucial role of tenascins is highlighted by the symptoms present in their absence – namely a form of Ehlers–Danlos syndrome.[1],[12]

Thrombospondin is also group of adhesion modulating glycoproteins well-distributed in the ECM.


Another crucial class of players in the ECM is the proteoglycans. As a structural category, they consist of a core protein with any number of attached glycosaminoglycans, which are unbranched, repeating disaccharide complexes.[24] Once assembled, proteoglycans can either be secreted into the ECM or embed into the plasma membrane of a local cell. Regardless of their final resting place, however, it is the GAG component of the structure that will be the primary interfacer with the ECM environment. In preparation for this role, they undergo a number of posttranslational modifications – such as acetylation and sulfation – to specify their future function in specific ligand binding.[25] Due to the number of possible permutations in proteoglycan structure, it is little surprise that they play a number of diversified roles in ECM function. Notable roles include hydration of the ECM, compression resistance, and mediation in signal factor binding. Membrane-bound betaglycan, for example, is known to bind and present activated TGF-beta to its receptor. Other proteoglycans, like syndecan, serve as part of the scaffolding networking, connecting other elements of the ECM like fibrillin and fibronectin.[24] Recently, there has been a discussion of the role of aberrant proteoglycan production in a form of progeroid Ehlers–Danlos syndrome, underscoring the importance of proteoglycans in maintaining ECM integrity.[25]

Extracellular matrix pathologies

It is important to realize that ECM composition is not the same across body systems. Regional ECM characteristics are in fact a defining characteristic of tissue classifications, serving critical roles in the functional integrity of the associated tissue. The ratio of fibers, linkers, and overall quantity of ECM create unique patterns that support a tissue's inherent function.[12] Naturally, disruption of these patterns often results in pathology. In the interest of the patient's presentation, we will use our discussion of ECM structure as a foundation to discuss pertinent ECM maintenance and production processes whose malfunction might lend to his observed symptomology. While some of these components are already linked to known CT disease already ruled out of our patient's differential by genetic testing, we offer a discussion as to why they are still viable options for the patient.

Possible causes of the patient's symptoms

Transforming growth factor-beta pathway

The role of TGF-beta in ECM regulation is difficult to overstate. Secreted as a latent homodimer from fibroblasts, TGF-beta is a multifunctional cytokine with roles from early embryological development through senescence. While the details are beyond the scope of this paper, we also note that TGF-beta comes in several isoforms, numbered 1, 2, and 3. While each plays an active role in pathological processes, our discussion will primarily focus on TGF-beta 1 as it is most implicated in chronic and systemic conditions.

Before activation, TGF-beta is bound by latent TGF-beta binding protein (LTBP), who naturally lies in close connection with the ECM – the specificities of which will be discussed later.[26] Thus the ECM is a prominent site of TGF-beta localization, underscoring TGF-beta's importance in ECM maintenance. Once activated – the means of which is beyond the scope of this paper – TGF-beta sheds LTBP and, via mediators such as betaglycan, decorin, or tenascin-X, binds to one of its many TGF-beta receptors.[24]

Once bound, the activated receptor will trigger an intracellular cascade to initiate a change in gene expression via tissue-specific pathways. In the canonical pathway, the process begins with the binding of a homodimer Type II receptor, triggering an autophosphorylation event that will ultimately activate a nearby Type I receptor. It is this latter receptor that will begin an intracellular Smad pathway, involving a combination of Smads1, 2, 3, 5, and 8, depending on the Type I receptor's subclass, which is a tissue dependent property. Regardless of the activation system, however, the cumulative result is the activation of Smad4, a nuclear-translocating transcription factor that can alter gene expression, including functions that regulate ECM signaling and regulatory proteins.[27]

As a brief aside, we must also note that the literature currently support the function of TGF-beta in noncanonical pathways, including those that do not involve Smad, Type II receptors, or Type I receptors.[27] Most notable among this lineage of pathways is their function in degrading rather than maintaining ECM. This has profound implication in CT pathology. Evidence from murine studies suggests that the TGF-beta signaling pathway in Marfan genotyped mice is rerouted through a noncanonical TGF-beta activin receptor-like kinase/Smad1/5/8 pathway, degrading the ECM to produce classic MF symptoms. We can take from these studies the possibility of an imbalance between canonical and noncanonical TGF-beta signaling as a possible inducer of the symptoms observed in our patient.[28] For a comparison of these two pathways, see [Figure 2].
Figure 2: Canonical pathway: Binding of transforming growth factor beta to transforming growth factor-beta receptor 2 induces receptor phosphorylation, recruiting a type 1 receptor subtype (transforming growth factor-beta receptor 1 or activin receptor-like kinase-1). This initiates a phosphorylation cascade that will ultimately alter gene transcription. Noncanonical pathway: p38MAPK phosphorylates Smad2, 3 independently of TGF-beta binding to change gene transcription. Other proposed noncanonical pathways include single subunit receptor signaling and activation of other pathways via Smad2, 3

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TGFBR1 and TGFBR2 mutations have also been noted to present CT manifestations, many classified as variants of LDS.[5] Interestingly, while the specific mutation seen in LDS is known to create defective receptors, mouse models suggest that Smad2 is unexpectedly upregulated, resulting in pathology.[29] While the mechanism for this is uncertain, it is hypothesized mutations in the TGF-beta receptors actually increase ligand binding.[27] This yields credence to the chance for another, yet unidentified player in the downstream TGF-beta pathway whose dysfunction could produce the patient's widespread symptomology.

Additional transforming growth factor-beta pathway factors

There are other factors in the TGF-beta complex that must also be considered suspect in the patient's pathology. It has been noted that several aberrant polymorphisms in LTBP4 manifest in CT like pathology, resulting in unnamed presentations of arterial, gastrointestinal, lung, and skin conditions such as are common in CT conditions.[13] This is not a surprise, as LTBP4 is closely associated to fibrillin-1, the culprit of Marfan's syndrome. Given the Marfinoid presentation of our patient, we can surmise that LTPB4 is a viable perpetrator of his condition.

Tenascins as well play an intimate role in TGF-beta signaling. An integrin and collagen binder, the actual mechanism by which tenascin-X works is unknown. However, mutations in tenascin-X are noted as the cause of Ehlers–Danlos, the hypermobility type, verifying its necessity for normal functioning CT. In addition, research on murine models with silenced TN-X present with normal fibroblast derived collagen synthesis, but abnormal organization into the ECM.[30] Assuming TN-X is normal in our patient, this deficiency points two a few possible culprits – the fibroblasts themselves or some unknown mediator in TN-X's signaling pathway or interactions. Bornstein and Sage offer a convincing hypothesis concerning TN-X and TGF-beta signaling. In their model, TN-X physically presents the latent TGF-beta complex to cellular integrins – possibly betaglycan - subsequently activating TGF-beta and the TGF-beta receptors.[31],[20] While all portions of this hypothesized pathway are not certain, this link between pathways yields further support for a TGF-beta connected signaling deficit in outpatient.


The role of proteoglycans, being highly diversified, makes this class of ECM modulatory suspect in our patient's pathology. In a discussion of a possible proteoglycan-derived Ehlers–Danlos condition, Miyake et al. proposed the role of aberrant decorin in the deregulation of collagen formation, resulting in a lack of functional collagen in a group of undiagnosed patients CT disease manifestations.[25] We can similarly propose that a deregulation of a proteoglycan, such as the TGF-beta involved factors decorin, betaglycan, or syndecan, would present with symptoms like those seen in our patient. The research needed to conclusively pin a highly suspect proteoglycan is still lacking, however, as is our understanding of proteoglycan pathogenesis. For example, decorin is also indicted in a congenital stromal dystrophy and betaglycan in renal cell carcinoma.[20],[21] Nonetheless, manifestation of these diverse conditions does not rule out the possibility of their pathogenesis in ECM-related deregulation. It is indeed possible that the specific location of a genetic polymorphism within the gene sequence for any one of these proteoglycans dictates the degree of pathological manifestation across organ systems.

Fibulins and associated factors

The fibulin family is recognized for its regulatory and linking functions in the ECM. With one binding domain associated with elastin and collagen, fibulins 2, 4, and 5 also are known to interact with fibrillin 1 and 4, who themselves interact directly with elastin. Mutations in fibulin 4 appear most promising for the patient's presentation, with one study suggesting a cutis-laxa like condition with subsequent pectus excavatum, arterial tortuosity, aneurysm, and lung complication in patients with aberrant fibulin-4.[32] While the patient does not present with the key cutaneous symptoms of cutis laxa, the similar symptom presentation compels a deeper look at fibulin interactions. The extent of current research recognizes that fibulins are secreted by fibroblasts and cross-link elastin fibers via interaction with LOX (lysyl oxidase). It is possible that a mutation to either LOX or a fibulin could present with elastin abnormalities similar to what we would see in other elastin-derived CT conditions, such as Ehlers–Danlos.[33] More research on the function effect of these proteins will better elucidate the systemic consequences of mutations.


The commonality behind all of the pathways we have discussed thus far is their intimate relationship with fibroblasts. Therefore, we can imagine that a deregulation in fibroblast activity, causing either excess production or reduced production of any of the above-listed factors, would cause a CT abnormality. An understanding of this would require a complete layout of the signaling pathways for each of the factors mentioned in this paper, which is too broad for our purposes. However, we note that fibroblasts are notable producers of TGF-beta as well as a known culprit behind lung cysts, which are prominent in our patient. We must therefore also consider the possibility of a fibroblastic role as either overrepresented presence or an overactive producer.[34]

  Conclusion Top

Given the systemic manifestations of the patient's symptom, the etiological source of his condition is likely rooted in CT abnormality. In narrowing down the most possible culprit for future study, we must distinctly note the widespread nature of his symptoms. Whatever his ECM aberration may be, it must involve a factor that is diffusely present and active, contributing to repeated damage in highly varied organ systems. While the degree of collagen, elastin, proteoglycans, and ECM contributors vary by organ system, the action of TGF-beta is not confined to a body region. Whether by direct physical interaction or consequential modulation, all of the players we have discussed play a role in the TGF-beta pathway. We therefore propose that our patient possesses some abnormality dependent on TGF-beta signaling. While this in its own is a broad diagnosis, it is our hope that this paper will spur additional research to help us and the medical community better hone our diagnostic and treatment protocols for patients like ours.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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