Extracellular Matrix Disorders Research Articles

Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects. This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein. We exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin. Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells. These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

The plasticity of fibroblasts: A forgotten player in the aging process.

Tissue-resident fibroblasts are mesenchymal cells which possess an impressive plasticity in their ability to modify their properties according to the requirements of the microenvironment. There are diverse subgroups of fibroblast phenotypes associated with different tissue pathological conditions, e.g., cancers, wound healing, and many fibrotic and inflammatory conditions. The heterogeneous phenotypes can be subdivided into fibrogenic and non-fibrogenic, inflammatory and immunosuppressive subtypes as well as cellular senescent subsets. A major hallmark of activated fibroblasts is that they contain different amounts of stress fibers combined with α-smooth muscle actin (α-SMA) protein, i.e., commonly this phenotype has been called the myofibroblast. Interestingly, several stresses associated with the aging process are potent inducers of myofibroblast differentiation, e.g., oxidative and endoplasmic reticulum stresses, extracellular matrix (ECM) disorders, inflammatory mediators, and telomere shortening. Accordingly, anti-aging treatments with metformin and rapamycin inhibited the differentiation of myofibroblasts in tissues. There is evidence that the senescent phenotype induced in cultured fibroblasts does not represent the phenotype of fibroblasts in aged tissues. Considering the versatile plasticity of fibroblasts as well as their frequency and structural importance in tissues, it does seem that fibroblasts are overlooked players in the aging process.

Growth plate extracellular matrix defects and short stature in children.

Many etiological factors causing short stature have already been identified in humans. In the last few years, the advent of new techniques for the detection of chromosomal and molecular abnormalities has made it possible to better identify patients with genetic causes of growth failure. Some of these factors directly affect the development and growth of the skeleton, since they damage the epiphyseal growth plate, where linear growth occurs, influencing chondrogenesis. In particular, defects in genes involved in the organization and function of the growth plate are responsible for several well-known conditions with short stature. These genes play a pivotal role in various mechanisms involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. In this review, we will discuss the genes involved in extracellular matrix disorders. The identification of genetic defects in linear growth failure is important for clinicians and researchers in order to improve the care of children affected by growth disorders.

The Role of the Stromal Extracellular Matrix in the Development of Pterygium Pathology: An Update.

Pterygium is a benign fibrovascular lesion of the bulbar conjunctiva with frequent involvement of the corneal limbus. Its pathogenesis has been mainly attributed to sun exposure to ultraviolet-B radiation. Obtained evidence has shown that it is a complex and multifactorial process which involves multiple mechanisms such as oxidative stress, dysregulation of cell cycle checkpoints, induction of inflammatory mediators and growth factors, angiogenic stimulation, extracellular matrix (ECM) disorders, and, most likely, viruses and hereditary changes. In this review, we aim to collect all authors’ experiences and our own, with respect to the study of fibroelastic ECM of pterygium. Collagen and elastin are intrinsic indicators of physiological and pathological states. Here, we focus on an in-depth analysis of collagen (types I and III), as well as the main constituents of elastic fibers (tropoelastin (TE), fibrillins (FBNs), and fibulins (FBLNs)) and the enzymes (lysyl oxidases (LOXs)) that carry out their assembly or crosslinking. All the studies established that changes in the fibroelastic ECM occur in pterygium, based on the following facts: An increase in the synthesis and deposition of an immature form of collagen type III, which showed the process of tissue remodeling. An increase in protein levels in most of the constituents necessary for the development of elastic fibers, except FBLN4, whose biological roles are critical in the binding of the enzyme LOX, as well as FBN1 for the development of stable elastin. There was gene overexpression of TE, FBN1, FBLN5, and LOXL1, while the expression of LOX and FBLN2 and -4 remained stable. In conclusion, collagen and elastin, as well as several constituents involved in elastic fiber assembly are overexpressed in human pterygium, thus, supporting the hypothesis that there is dysregulation in the synthesis and crosslinking of the fibroelastic component, constituting an important pathogenetic mechanism for the development of the disease.

Transforming Growth Factor Beta 1 and p44/42 Expression in Cardinal Ligament Tissues of Patients with Pelvic Organ Prolapse.

BackgroundPelvic organ prolapse (POP) is a disease associated with collagen loss and decreased fibroblast proliferation. Transforming growth factor beta 1 (TGF-β1) controls collagen synthesis and degradation in pelvic connective tissue. Although the p44/42 MAPK pathway has been implicated in collagen production and extracellular matrix disorders, its expression in POP remains unknown. This study aimed to investigate TGF-β1 and p44/42 expression in cardinal ligament tissues in patients with POP.Material/MethodsCardinal ligament tissues were obtained from 30 patients with POP (POP group) and 30 patients with benign gynecological disorders who had undergone total hysterectomy (control group). The clinical characteristics of the 2 groups were summarized. Immunohistochemical staining and western blotting analysis were performed to measure the expression of TGF-β1, p44/42, phospho-p44/42, MMP9, TIMP1, caspase 3, collagen I, and collagen III in the cardinal ligament tissues.ResultsPatients with POP had significantly lower TGF-β1 and phospho-p44/42 levels than did control patients (P<0.05). The expression of TIMP1, collagen I, and collagen III was significantly lower, and the expression of MMP9 and caspase 3 was significantly higher in the POP group than in the control group (P<0.05). Moreover, the expression of phospho-p44/42 was positively correlated with the expression of TGF-β1, collagen I, and collagen III.ConclusionsThe expression levels of phospho-p44/42 and TGF-β1 were decreased in patients with POP and were positively correlated with collagen expression. Low levels of TGF-β1 and phospho-p44/42 expression in patients with POP may be associated with the occurrence of POP.

Downregulation of the Yes-Associated Protein Is Associated with Extracellular Matrix Disorders in Ascending Aortic Aneurysms.

Previous studies indicate that extracellular matrix (ECM) disorders lead to the apoptosis of Vascular Smooth Muscle Cells (VSMCs), which impairs the aortic wall by reducing the generation of elastic fibers, and ultimately result in ascending aortic aneurysm. The critical role of the Yes-associated protein (YAP) has been elucidated in cardiac/SMC proliferation during cardiovascular development. However, the association of YAP expression and extracellular matrix disorders in ascending aortic aneurysms is not clear. Here, we present for the first time that the downregulation of YAP in VSMCs is associated with ECM disorders of the media in ascending aortic aneurysms. We found that aortic ECM deteriorated with increased apoptotic VSMCs. Moreover, expression of YAP was dramatically reduced in the aortic walls of patients with ascending aortic aneurysms, while the normal aortic samples exhibited abundant YAP in the VSMCs. These results suggest that downregulation of YAP leads to apoptosis of VSMCs, which are essential for the homeostasis of the aortic wall. The resultant ECM disorders affect aortic structure and function and contribute to the development of ascending aortic aneurysms. In summary, through assessment of clinical samples, we revealed the association between downregulation of YAP in VSMCs and the development of ascending aortic aneurysms, providing new insight into the pathogenesis of this disease.

The neuromuscular differential diagnosis of joint hypermobility.

Joint hypermobility is the defining feature of various inherited connective tissue disorders such as Marfan syndrome and various types of Ehlers-Danlos syndrome and these will generally be the first conditions to be considered by geneticists and pediatricians in the differential diagnosis of a patient presenting with such findings. However, several congenital and adult-onset inherited myopathies also present with joint hypermobility in the context of often only mild-to-moderate muscle weakness and should, therefore, be included in the differential diagnosis of joint hypermobility. In fact, on the molecular level disorders within both groups represent different ends of the same spectrum of inherited extracellular matrix (ECM) disorders. In this review we will summarize the measures of joint hypermobility, illustrate molecular mechanisms these groups of disorders have in common, and subsequently discuss the clinical features of: 1) the most common connective tissue disorders with myopathic or other neuromuscular features: Ehlers-Danlos syndrome, Marfan syndrome and Loeys-Dietz syndrome; 2) myopathy and connective tissue overlap disorders (muscle extracellular matrix (ECM) disorders), including collagen VI related dystrophies and FKBP14 related kyphoscoliotic type of Ehlers-Danlos syndrome; and 3) various (congenital) myopathies with prominent joint hypermobility including RYR1- and SEPN1-related myopathy. The aim of this review is to assist clinical geneticists and other clinicians with recognition of these disorders.

Advances in understanding and treating dystrophic epidermolysis bullosa.

Epidermolysis bullosa is a group of inherited disorders that can be both systemic and life-threatening. Standard treatments for the most severe forms of this disorder, typically limited to palliative care, are ineffective in reducing the morbidity and mortality due to complications of the disease. Emerging therapies—such as the use of allogeneic cellular therapy, gene therapy, and protein therapy—have all shown promise, but it is likely that several approaches will need to be combined to realize a cure. For recessive dystrophic epidermolysis bullosa, each particular therapeutic approach has added to our understanding of type VII collagen (C7) function and the basic biology surrounding the disease. The efficacy of these therapies and the mechanisms by which they function also give us insight into developing future strategies for treating this and other extracellular matrix disorders.

Allogeneic Hematopoietic Cell Transplantation for Severe Epidermolysis Bullosa: Impact of Conditioning Regimen and Stem Cell Source On Outcomes

AbstractAbstract ▪965▪This icon denotes a clinically relevant abstractIt is becoming clear that bone marrow (BM) and umbilical cord blood (UCB) cells can engraft in extramedullary tissues after hematopoietic cell transplantation (HCT). On the basis of preclinical testing in an animal model of recessive dystrophic epidermolysis bullosa (RDEB, an incurable, often fatal blistering genodermatosis), we evaluated the effectiveness of allogeneic HCT in ameliorating the biochemical and clinical manifestations of the disease in humans. RDEB is due to deficiency of type VII collagen (C7), which causes a lack of attachment between the epidermal basement membrane and the dermal matrix, and which results in a poor quality of life and early death as a result of chronic mucocutaneous blistering. Between 2007 and 2012, 18 patients with severe generalized RDEB have undergone allogeneic HCT at the University of Minnesota. Thirteen patients were treated with myeloablative (MA) conditioning (busulfan IV 0.8 mg/kg for >12 kg and 1.1 mg/kg for those <12 kg of body weight every 6 hours on days -9 to -6, with pharmacokinetic targeting 1,000 mmol/min for the area under curve; fludarabine [FLU] IV 25 mg/m2/day on days -5 to -3; and cyclophosphamide [CY] IV 50 mg/kg/day on days -5 to -2). Five patients were treated with non-MA conditioning (CY IV 50 mg/kg/day on day -6; FLU IV 40 mg/m2/day on days -6 to -2; anti-thymocyte globulin IV 30 mg/kg/day on days -4 to -2; and total body irradiation 200 cGy on day -1), with cyclosporine A and mycophenolate mofetil as GVHD prophylaxis. Patients were transplanted with either BM from an HLA-matched sibling (n=10) or HLA-matched unrelated donor (n=3), or with partially matched UCB (n=5) when a matched marrow donor was not available. In addition to the hematopoietic graft, a single infusion of third-party, HLA-mismatched mesenchymal stromal/stem cells (MSCs, dose: 2 × 106/kg) was administered on day 0 to 12 of the 18 RDEB individuals (7 with MA and 5 with non-MA conditioning). The primary endpoint of the analysis was survival with skin improvement. Importantly, non-MA conditioning was well tolerated, with a marked reduction in risk of infection, and of pulmonary and renal toxicity. Thus far, for the entire cohort, the overall probability of survival is 73% (95% CI, 49–96%), with 11 patients demonstrating partial-to-marked biochemical and clinical improvement in mucocutaneous disease as evaluated by protein expression and resistance to blistering. There are no significant differences yet in beneficial or adverse effects in patients treated with or without MSC co-infusion. Transplant outcomes are shown in the Table.GraftNRegimenNC7 Protein ExpressionSkin Healing1Skin Chimerism, N (range)3GvHD Acute/ChronicAliveAlive and EngraftedUCB5MA4211 (11–30%)1/121RIC10000/010BM13MA96727 (2–97%)1/077RIC41322 (3–23%)0/044Total18181011102/11411We conclude that BM is the preferred source of HSC (BM: 11 of 13 alive and engrafted [85%] versus CB: 1 of 5 alive and engrafted [20%], p-value = 0.02). Also, early results with the non-MA conditioning are promising in terms of toxicity profile and engraftment. Overall, HCT can result in significant skin engraftment, restoration of the missing C7 protein, and clinical improvement in RDEB. HCT has the potential of being a durable, systemic therapy for many people with different forms and severities of EB, and sets the stage for using BM cells in the treatment of a broad spectrum of extracellular matrix disorders.1Defined as a change in the amount of skin covered with blisters and erosions from >50% before HCT to <10% after HCT.2Remarkably, significant clinical improvement can be achieved even in the absence of any detectable C7 early after HCT.3Approximately 30% of wild-type levels of C7 are believed to be sufficient to protect from extensive blistering. Disclosures:No relevant conflicts of interest to declare.

Laser-treatedNucleus pulposusas an innovative model of intervertebral disc degeneration

This study describes an innovative experimentally induced model of intervertebral disc degeneration. This innovative approach is based on the induction of extracellular matrix disorders in the intervertebral disc (IVD) using a diode laser. For this study, 15 one-year-old and five 30-month-old New Zealand White rabbits were used. Two procedures were tested to trigger IVD degeneration: needle aspiration (reference technique) and a laser approach. The IVD degeneration process was assessed 20, 40, 60, 90 and 120 days after surgery by X-ray radiography (IVD height), magnetic resonance imaging (MRI) (T2 intensity of IVD signal) and histological analysis using modified Boos' scoring. Our data indicate that a marked IVD degeneration was found compared with sham-operated animals regardless of the procedure tested. A significant decrease in disc height on X-ray radiographs was first demonstrated. In addition, MRI disc signals were significantly reduced in both groups. Finally, a statistically significant increase in Boos' scoring was found in both laser and aspiration-induced IVD degeneration. Interestingly, IVD degeneration induced by laser treatment was more progressive compared with aspiration. Moreover, the histological results indicated that laser-induced disc degeneration was quite similar to that obtained during the natural aging process as observed in 30-month-old rabbits. Our study describes the consistency of this innovative experimentally-induced animal model of IVD degeneration. The radiological, MRI and histological data confirm its relevance. The histological examination indicates that IVD degeneration induced by laser treatment is comparable to the degenerative process observed during the onset of spontaneous IVD degeneration. This model could be a useful tool to help us validate biomaterial-assisted, cell-based, regenerative medicine strategies for the prevention and treatment of IVD degeneration.

Association of smooth muscle cell phenotypes with extracellular matrix disorders in thoracic aortic dissection

Extracellular matrix dysregulation in the aortic media has been considered as the intrinsic factor for the formation of thoracic aortic dissection. However, the mechanisms of extracellular matrix disorders in the dissected aortic media remain unclear. This study was designed to investigate the relevance between smooth muscle cell phenotypes and extracellular matrix disorders in the dissected media. Their interaction may account for the pathogenesis of thoracic aortic dissection. Thoracic aortic samples were collected from 10 patients with thoracic aortic dissection and 10 controls. Primary cultures of aortic medial smooth muscle cells were obtained with optimized explant technique. In this study, α-smooth muscle actin, smooth muscle myosin heavy chain 2, and smoothelin were applied as the contractile phenotypic markers and osteopontin was applied as the synthetic marker. Compared with controls, immunostaining and immunoblotting demonstrated that in vivo expression of α-smooth muscle actin, smooth muscle myosin heavy chain 2, and smoothelin were significantly decreased in the dissected media, whereas that of osteopontin was elevated (P<.01 for all). In vitro expression of the phenotypic markers showed the similar patterns. Furthermore, smooth muscle cells derived from the dissected media exhibited enhanced proliferation (P<.01), increased collagens I and III synthesis (2.6- and 4.4-fold, respectively; P<.01 for both), and elevated matrix metalloproteinase-2 production (4.2-fold; P<.01). Consistently, the protein levels of type I and III collagens and matrix metalloproteinase-2 in the dissected media were raised by 4.6-, 4.0-, and 3.7-fold, respectively (P<.01 for all). Collagen deposition was correspondingly increased and elastic fibers were decreased and disrupted. Smooth muscle cells in the dissected media exhibit phenotypic switching from the contractile to the synthetic type. The synthetic smooth muscle cells increase collagen synthesis and matrix metalloproteinase-2 production, both of which can promote collagen deposition and elastin degradation in thoracic aortic dissection.

Reinventing mesenchymal stromal cells

The life-saving impact of chemotherapy and radiation has been as remarkable and momentous as any advance in the history of medicine. This becomes even more signifi cant when we remind ourselves that 50 years ago nearly all leukemias, lymphomas and aggressive solid tumors were fatal, and that nearly everything in oncology before the 20th century was a placebo. However, unintended collateral damage by chemotherapy and radiation to healthy tissues of patients has limited the benefi cial impact of these successes in oncology and in the related fi eld of hematopoietic cell transplantation (HCT). HCT has been a life-saving treatment for many patients with malignant as well as non-malignant, yet equally lethal, diseases and conditions, such as bone marrow failure (e.g. acquired idiopathic severe aplastic anemia, osteopetrosis, Fanconi anemia and dyskeratosis congenita), hemoglobinopathies (e.g. sickle cells disease and thalassemia), immunodefi ciencies (e.g. X-linked defi ciency in the common cytokine receptor gamma chain), and lysosomal (e.g. mucopolysaccharidosis type I – Hurler syndrome), peroxisomal (e.g. childhood cerebral adrenoleukodystrophy) and extracellular matrix (e.g. severe forms of epidermolysis bullosa) disorders (1,2). To limit tissue toxicity, in principle at least two major, but not mutually exclusive, approaches are possible: targeted therapy of cancer (e.g. Ph (Philadelphia (chromosome)) leukemia treatment with anti-BCR-ABL (Breakpoint Cluster Region-Abelson (gene)) antibody) (3) and targeted conditioning for HCT (e.g. immunoablation of hematopoietic stem cells with anti-c-kit antibody) (4); or injury protection and enhancement of tissue repair. During the last decade, the most popular cells for the latter concept have been mesenchymal stromal cells (MSC) (5). Their function in vivo is not well defi ned, but they are likely to be critical for a number of physiologic processes. One example is a support for blood-forming cells in the bone marrow hematopoietic niche, where they are ‘ a drugstore ’ , supplying neighboring cells with growth factors, adhesion molecules and homing cytokines. MSC can function as immune modulator cells and are being used extensively for the prevention and treatment of graft-versus-host disease, the main immune complication of HCT. Also, MSC home preferentially to sites of injury and, in several pre-clinical models and clinical trials of organ damage (e.g. heart, lung, kidney, pancreas, intestine, bone and skin), have been shown to mediate tissue healing. Contrary to original expectations, donor MSC do not appear to replace the damaged cells, but rather use paracrine mediators to recruit the recipients ’ cells into a regenerative microenvironment, which in turn limits apoptosis, promotes angiogenesis, and aids in productive tissue repair (6). Two recent reports in Cytotherapy explore this regenerative capability of human MSC in mice treated with high doses of radiation or chemotherapy. Di et al. (7) asked whether chemotherapy-induced injury in mice could be alleviated by infusion of MSC from human cord blood. They treated mice with doxorubicin, a chemotherapy medication associated with a stereotypical toxicity profi le in bone marrow, heart and intestines. Infusion of MSC not only decreased the degree of damage in these organs, but also increased overall survival in mice that had Cytotherapy, 2012; 14: 388–390

Induced Pluripotent Stem Cells from Individuals with Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disorder caused by mutations in the COL7A1 gene-encoding type VII collagen (Col7), the major component of anchoring fibrils at the dermal-epidermal junction. Individuals with RDEB develop painful blisters and mucosal erosions, and currently, there are no effective forms of therapy. Nevertheless, some advances in patient therapy are being made, and cell-based therapies with mesenchymal and hematopoietic cells have shown promise in early clinical trials. To establish a foundation for personalized, gene-corrected, patient-specific cell transfer, we generated induced pluripotent stem (iPS) cells from three subjects with RDEB (RDEB iPS cells). We found that Col7 was not required for stem cell renewal and that RDEB iPS cells could be differentiated into both hematopoietic and nonhematopoietic lineages. The specific epigenetic profile associated with de-differentiation of RDEB fibroblasts and keratinocytes into RDEB iPS cells was similar to that observed in wild-type (WT) iPS cells. Importantly, human WT and RDEB iPS cells differentiated in vivo into structures resembling the skin. Gene-corrected RDEB iPS cells expressed Col7. These data identify the potential of RDEB iPS cells to generate autologous hematopoietic grafts and skin cells with the inherent capacity to treat skin and mucosal erosions that typify this genodermatosis.

Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells

AbstractThe recessive dystrophic form of epidermolysis bullosa (RDEB) is a disorder of incurable skin fragility and blistering caused by mutations in the type VII collagen gene (Col7a1). The absence of type VII collagen production leads to the loss of adhesion at the basement membrane zone due to the absence of anchoring fibrils, which are composed of type VII collagen. We report that wild-type, congenic bone marrow cells homed to damaged skin, produced type VII collagen protein and anchoring fibrils, ameliorated skin fragility, and reduced lethality in the murine model of RDEB generated by targeted Col7a1 disruption. These data provide the first evidence that a population of marrow cells can correct the basement membrane zone defect found in mice with RDEB and offer a potentially valuable approach for treatment of human RDEB and other extracellular matrix disorders.

Tissue-specific Changes in the Hydroxylysine Content and Cross-links of Collagens and Alterations in Fibril Morphology in Lysyl Hydroxylase 1 Knock-out Mice

We have generated mice with targeted inactivation of the Plod1 gene for lysyl hydroxylase 1 (LH1). Its human mutations cause Ehlers-Danlos syndrome VIA (EDS VIA) characterized by muscular hypotonia, joint laxity, and kyphoscoliosis. The Plod1(-/-) mice are flaccid and have gait abnormalities. About 15% of them died because of aortic rupture and smooth muscle cells in non-ruptured Plod1(-/-) aortas showed degenerative changes. Collagen fibrils in the Plod1(-/-) aorta and skin had an abnormal morphology. The LH activity level in the Plod1(-/-) skin and aorta samples was 35-45% of that in the wild type. The hydroxylysine content was decreased in all the Plod1(-/-) tissues, ranging from 22% of that in the wild type in the skin to 75 and 86% in the femur and lung. The hydroxylysylpyridinoline crosslinks likewise showed decreases in all the Plod1(-/-) tissues, ranging from 28 and 33% of that in the wild type in the aorta and cornea to 47 and 59% in femur and tendon, while lysylpyridinolines were increased. The hydroxylysines found in the Plod1(-/-) collagens and their cross-links were evidently synthesized by the other two LH isoenzymes. Few data are available on abnormalities in EDS VIA tissues other than the skin. Plod1(-/-) mice offer an in vivo model for systematic analysis of the tissue-specific consequences of the lack of LH1 activity and may also provide a tool for analyzing the roles of connective tissue in muscle function and the complex interactions occurring in the proper assembly of the extracellular matrix.

The biology of hernias and the abdominal wall

The fundamental mechanism for hernia formation is loss of the mechanical integrity of abdominal wall structural tissue that results in the inability to offset and contain intra-abdominal forces during valsalva and loading of the torso. There is evidence that genetic or systemic extracellular matrix disorders may predispose patients to hernia formation. There is also evidence that acute laparotomy wound failure leads to hernia formation and increases the risk of recurrent hernia disease. It may be that hernia formation is a heterogeneous disease, not unlike cancer, where one population of patients express an extracellular matrix defect leading to primary hernia disease, while other subsets of patients acquire a defective, chronic wound phenotype following failed laparotomy and hernia repairs. It is evident that an improved understanding of structural tissue matrix biology will lead to improved results following abdominal wall reconstructions.

Reflections on reduction ascending aortoplasty's liveliness

Reflections on reduction ascending aortoplasty's liveliness

Serum elastase activity is elevated in migraine

Migraine has been associated with diseases considered to be related to extracellular matrix disorders--in particular, cervical artery dissection. In this population-based study, we found a highly significant association between migraine and the activity of serum elastase, a metalloendopeptidase degrading specific elastin-type amino acid sequences. Such enzymes are involved in matrix degradation. This association was seen in both sexes and was stronger for migraine with aura. These findings could help in the understanding of why patients with migraine are at higher risk of stroke. Further study is needed to establish whether extracellular matrix abnormalities play a broader role in the pathophysiology of migraine.

Serum elastase activity is elevated in migraine

Migraine has been associated with diseases considered to be related to extracellular matrix disorders—in particular, cervical artery dissection. In this population-based study, we found a highly significant association between migraine and the activity of serum elastase, a metalloendopeptidase degrading specific elastin-type amino acid sequences. Such enzymes are involved in matrix degradation. This association was seen in both sexes and was stronger for migraine with aura. These findings could help in the understanding of why patients with migraine are at higher risk of stroke. Further study is needed to establish whether extracellular matrix abnormalities play a broader role in the pathophysiology of migraine. Ann Neurol 2000;47:648–651