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PubMed1978

Free serum ribonucleoprotein in mixed connective tissue disease and other connective tissue diseases.

Free ribonucleoprotein (RNP) was found by means of a hemagglutination inhibition assay in 21 sera from 11 of 25 patients with mixed connective tissue disease (MCTD) who had 299 sera studied. Free RNP tended to appear when anti-RNP antibody titers fell or when prednisone was initiated or increased. Five of 72 SLE patients (211 sera) had free RNP in at least one serum. Three of them had anti-RNP antibodies in other sera. Free serum RNP was found in one of 20 patients with scleroderma and in two of seven patients with connective tissue disease "overlap" syndromes without anti-RNP.

Antibodies, Antinuclear↗
PubMed1999

Propagation in cardiac tissue adjacent to connective tissue: two-dimensional modeling studies.

The conditions for activation transmission across a region of extracellular space was demonstrated in two-dimensional preparations with results consistent with those previously seen in the one-dimensional fiber studies. In addition, one sees changes in action potential morphology which occur in the tissue nearest the connective-tissue border as well as changes in conduction velocity along the border. These results hinge on an adequate representation of the connective-tissue region achieved by careful implementation of the boundary conditions in the intracellular and interstitial spaces and the expansion of the connective-tissue discretization to a "double-tier network" description. Through a series of simulations, a clear dependence on fiber orientation is illustrated in the efficacy to transmit activation. The collision of a front with an embedded connective-tissue region was also examined. The results revealed that fibers aligned normal to a planar stimulus would more greatly disrupt the advancement of a planar front. Such pronounced disruptions have been shown to be proarrhythmic in the literature. The increasing evidence of the ability of connective tissue to transmit activation has implications in understanding spread of activation through infarcted tissues and through the healthy ventricular wall in the presence of connective-tissue sheets.

Action Potentials↗
PubMed1996

Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor.

Connective tissue growth factor (CTGF) is a 36-to 38-kDa peptide that is selectively induced by transforming growth factor-beta (TGF-beta) in fibroblastic cell types. We compared the biologic activities of CTGF with TGF-beta on fibroblasts in culture and in animal models of fibroplasia. CTGF was active as a mitogen in monolayer cultures of normal rat kidney fibroblasts. CTGF did not stimulate anchorage-independent growth of NRK fibroblasts, however, or inhibit the growth of mink lung epithelial cells, distinguishing CTGF's growth-regulatory activities from those of TGF-beta. In NRK fibroblasts, both TGF-beta and CTGF significantly increased the transcripts encoding alpha 1 type I collagen, alpha 5 integrin, and fibronectin. Stimulation of type I collagen and fibronectin protein synthesis by TGF-beta and CTGF was confirmed by pulse labeling of cells with [35S]methionine. Subcutaneous injection of TGF-beta and CTGF into neonatal NIH Swiss mice resulted in a large stimulation of granulation tissue and fibrosis at the site of injection. In situ hybridization studies revealed that TGF-beta injection induced high levels of CTGF mRNA in the dermal fibroblasts at the injection site, demonstrating that TGF-beta can induce the expression of CTGF in connective tissue cells in vivo. No CTGF transcripts were detected in the epidermal cells in either control or TGF-beta-injected skin or in fibroblasts in control (saline-injected) skin. These results demonstrate that, like TGF-beta, CTGF can induce connective tissue cell proliferation and extracellular matrix synthesis.

Animals↗
PubMed1992

Connective tissue activation. XXXV. Detection of connective tissue activating peptide-III isoforms in synovium from osteoarthritis and rheumatoid arthritis patients: patterns of interaction with other synovial cytokines in cell culture.

OBJECTIVE: To determine whether extracts of unincubated osteoarthritis (OA) and rheumatoid arthritis (RA) synovial tissue contain connective tissue activating peptide-III (CTAP-III) isoforms and prostaglandin E2 (PGE2), and whether such extracts have growth-promoting activity, and to determine whether binary combinations of CTAP-III with other cytokines reported to be present in synovial tissue lead to synergistic, additive, or inhibitory effects on growth. METHODS: Acid-ethanol extracts of human synovium were examined for growth-promoting activity by measuring formation of 14C-glycosaminoglycan (14C-GAG) and 3H-DNA in synovial cell cultures; PGE2 was measured by enzyme immunoassay, and CTAP-III isoforms were identified by Western blotting of extracted proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Growth-promoting activity of CTAP-III and other cytokines was tested in synovial cultures treated with the agonists singly and in binary combination, by measuring changes in synthesis of 14C-GAG and 3H-DNA. RESULTS: Platelet-derived CTAP-III and a cleavage isoform with the electrophoretic mobility of CTAP-III-des 1-15/neutrophil-activating peptide-2 (NAP-2) and PGE2 were found in biologically active extracts of synovial samples from patients with RA and OA. Five growth factors (recombinant epidermal growth factor [rEGF], recombinant interleukin-1 beta [rIL-1 beta], basic fibroblast growth factor [bFGF], PGE1, and PGE2) in binary combination with CTAP-III showed synergism in stimulating GAG synthesis; two (recombinant platelet-derived growth factor type BB [rPDGE-BB] and recombinant transforming growth factor beta [rTGF beta]) had an additive effect. In combination with CTAP-III, rEGF and rPDGF-BB had a synergistic effect in promoting DNA synthesis, rTGF beta and rbFGF had an additive effect, and rIL-1 beta, PGE1, and PGE2 were antagonistic. CONCLUSIONS: The results suggest that, in addition to endogenous factors, CTAP-III and other platelet-derived cytokines may play roles in regulating synovial cell metabolism in RA and OA, and that combinations of growth factors may be more significant than single agents in amplification or suppression of important cell functions.

Arthritis, Rheumatoid↗
PubMed1991

Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease.

We identified a cohort of 410 patients with connective tissue disorders (CTD) of less than or equal to 1 year duration among the participating clinics of the Cooperative Systematic Studies of the Rheumatic Diseases Program. Fifty-seven had rheumatic arthritis (RA), 57 systemic lupus erythematosus, 37 poly/dermatomyositis, 46 scleroderma, and 213 early undifferentiated CTD, including patients with Raynaud's phenomenon, unexplained polyarthritis or at least 3 CTD manifestations such as rashes, myalgias, etc. Baseline clinical data are now being reported. The followup of these patients may prove to be valuable in understanding these diseases. To our knowledge no similar cohort of patients is available for further investigation.

Adolescent↗
PubMed1983

The application of quantitative cytochemistry to the study of diseases of the connective tissues.

The connective tissues are a complex organisation of tissues, cells and intercellular materials spread throughout the body and are subject to a large number of diseases. Such complexity makes the study of the metabolism of the connective tissues in health and more particularly in disease states difficult if one uses conventional biochemical methodology. Fortunately the techniques of quantitative cytochemistry, as developed in recent years, have made it possible to study the metabolism of even such complex and refractory connective tissues as bone. Using properly validated assays of enzyme activity in unfixed sections from various tissues a number of the diseases of the connective tissues have been studied. For example the synovia from patients with rheumatoid arthritis and related conditions have been studied using these techniques and marked alterations in the metabolism of the synovial lining cell population of this tissue have been demonstrated. These alterations in metabolism are believed to be related to the destruction of cartilage and bone found in such diseases. Investigations of the metabolism of the chondrocytes of articular cartilage in a strain of mice which spontaneously develops osteoarthritis has revealed a lack of certain key enzymes of carbohydrate metabolism in precisely those areas where degradation of the matrix of articular cartilage begins suggesting a causal relationship between these events. These same techniques have been used to study the cellular kinetics and metabolism of the dermis and epidermis in the disfiguring disease, psoriasis. The metabolism of healing bone fractures, the diagnosis and treatment of the mucopolysaccharidoses and the metabolic effects of currently used anti-inflammatory and anti-rheumatic drugs have also been examined. Perhaps the most exciting aspect of these studies has been the development and use of the technique of the cytochemical bioassay (CBA) to study hormonally mediated diseases of the connective tissues. Such studies have recently shed new light on the molecular lesion in pseudohypoparathyroidism. Though still in their relative infancy the studies described in this review show the potential inherent in the use of quantitative cytochemistry for the study of diseases of the connective tissues.

Animals↗
PubMed1996

Early undifferentiated connective tissue disease. IV.Musculoskeletal manifestations in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of patients with well-established connective tissue diseases: followup analyses in patients with unexplained polyarthritis and patients with rheumatoid arthritis at baseline.

OBJECTIVES: To examine the musculoskeletal manifestations in a large cohort of patients (n = 410) diagnosed with either a well-established connective tissue disease (CTD) (n = 197) or an early undifferentiated CTD (n = 213) with a symptom duration of <1 year. This study was aimed at determining the predictive value of demographic, clinical, and laboratory features on outcome in patients with unexplained polyarthritis (UPA) (from the early undifferentiated CTD cohort; n = 67) or rheumatoid arthritis (RA) (from the well-established CTD cohort; n = 57), over a 5-year followup period. METHODS: Patients from both cohorts were assessed at years 1, 3, and 5. At the study visits, clinical data were collected in a standardized manner, and sera were obtained and stored. A priori criteria were established for patient ascertainment and diagnosis over the duration of the study. Standard statistics were used for comparisons of baseline characteristics in patients diagnosed as having systemic lupus erythematosus, RA, undifferentiated CTD, and UPA at entry into the cohorts. Baseline features in patients with UPA were examined according to the different subsequent outcomes (RA, CTD, or undifferentiated CTD, remission [nonpersistent], or persistent or active UPA). Baseline features in patients with RA whose disease remained active versus those in whom remission was attained were also examined. Two multivariable analyses, classification trees and polychotomous logistic regression, were performed to predict disease outcomes over time. RESULTS: The overall rate of ascertainment for the 410 patients ranged from 90 % at year 1 to 71 % at year 5. Patients with established CTDs showed a tendency for more stable diagnoses than those with early undifferentiated CTDs (90-100% versus 45-70%). Consistent baseline predictors of persistent active disease among patients with RA, in both univariate and multivariable analyses, were higher joint counts for pain and tenderness and higher erythrocyte sedimentation rate (ESR). In approximately 20% of patients who were classified as having RA when they originally entered the cohort, the disease was in remission at 5 years. Twenty percent of the patients originally classified as having UPA developed RA over the duration of the study. These patients tended to be older and to have swelling of small joints at baseline. However, a consistent pattern of predictive variables could not be identified in the multivariable analyses, other than at year 1 (higher small joint counts for swelling and higher ESR). CONCLUSION: Baseline features (joint counts, and ESR) among RA patients were variously predictive of persistently active disease at years 1-5. Consistent baseline predictors of outcome among patients with UPA only emerged at year 1. Remission occurred in approximately 20% of RA patients, whereas a similar percentage of patients with UPA developed RA. These findings have implications with regard to treatment decisions in patients with early RA and/or UPA.

Adult↗
PubMed1993

[Connective tissue massage].

Connective tissue massage deals with the skin and the subcutaneous tissue. It focuses on definite regions of the body, assigned in segmental order to inner organ systems and structures of the locomotor system (spinal cord, joints, muscles). In case of acute disease, oedematous swelling of a generally soft tissue consistency can be observed in circumscribed areas. Persisting symptoms may result in induration of such tissues, associated with reduced rheology and epicritic pain if manipulated mechanically. Eventually, chronic conditions may progress to atrophy. The name "connective tissue massage" is based on the concept that corresponding physiological events take place in connective tissue structures and the segmentally associated organ. With regard to the pathophysiology of such zones, mechanisms which are comparable to sympathetic reflex dystrophy are discussed at present. Analysis of such changes has contributed to general diagnosis. Connective tissue massage is considered to be an important element of physiotherapy. The clinical data on the efficacy of connective tissue massage are reviewed.

Chronic Disease↗
PubMed1993

[Trigeminal neuropathy and connective tissue diseases].

Connective tissue diseases are a rare and poorly understood etiology of trigeminal neuropathy. In a retrospective multicentric study covering 12 years. 12 cases were identified in the archives of the Departments of Neurology, Rheumatology and Internal Medicine: 4 were associated with progressive systemic sclerosis. 4 with mixed connective tissue diseases and 4 with Sjögren's syndrome. In 9 of the cases, the neuropathy led to the diagnosis of connective tissue disease. Trigeminal neuropathy usually developed during the evolution of the connective-tissue disease but, in 3 cases, it preceded other clinical signs. As a rule, the connective tissue disease was relatively inactive when the trigeminal nerve was involved. The neuropathy was usually unilateral (9 times), localized to the inferior branch(es) of the trigeminal and manifested itself by an isolated sensation of cutaneous numbness associated with paresthesias. Only one patient had mixed motor and sensory involvement. The topography of the lesions (peripheral, truncal, radicular or central nuclear) remains unknown in most cases, however, electromyographic study of the blinking reflex in 2 patients confirmed peripheral neuropathy in both of them. Corticotherapy had only a minor effect: neuralgia was rare and carbamazepine was ineffective. The pathogenicity of trigeminal involvement is discussed and these observations are compared to the 151 cases reported in the literature.

Adult↗
PubMed1982

The structure and function of dermal connective tissue in normal individuals and patients with inherited connective tissue disorders.

Normal, human dermis is a dense, interwoven collagen and elastic matrix organized into papillary and reticular regions. the papillary dermis is a narrow zone beneath the epidermis which includes an even narrower subepidermal connective tissue band beneath the basal lamina. The reticular dermis has superficial intermediate and deep reticular zones. Each region is distinguished by the organization of the fibrous connective tissue. In this review, the structure, composition and function of each region of the normal dermis is surveyed and alterations in the tissue that have been recognized ultrastructurally in skin from patients with inherited connective tissue diseases are discussed. A molecular defect in a connective tissue molecule can be expressed phenotypically at one or more levels of dermal organization and can modify the structure of other matrix components. In some cases, the entire interwoven pattern of the dermis is altered; in others, the dermis retains the interwoven pattern and alterations are expressed as defects in the association of fibrils into fibers and fiber bundles. Abnormalities in the size, packing and relationships of fiber bundles also can occur. These changes involve the collagen matrix primarily. Depletion or exaggeration of elastin, or of the amorphous ground substance can also influence the organization of collagen and of the overall dermal architecture. The alterations described are illustrated with scanning electron micrographs of skin from patients with inherited connective disorders and are discussed in terms of the mechanical abnormalities of the tissue.

Collagen↗
PubMed1980

Current concepts in the classification of connective tissue diseases. Overlap syndromes and mixed connective tissue disease (MCTD).

New principles are discussed for the classification of the diffuse collagen diseases, particularly the mixed connective tissue disease (MCTD), with clinical and historical explanation. Emphasis in classification has shifted from a concern with tissue pathology to serologic anomalies, which may involve eleven different antigens, many from human cell nuclei. New serologic tests, such as the ribonucleoprotein (RNP) antibody test, may be superior to the well-known fluorescent antinuclear antibody (ANA) studies for diagnosis and follow-up of diffuse collagen diseases. Functional clinical studies, such as esophageal motility, gas exchange in the lung, and major joint mobility, which may appear early in MCTD, are more important to diagnosis than anatomic studies of late-developing lesions.

Connective Tissue Diseases↗
PubMed1988

A new long-term in vitro invasion assay using fibrous connective tissue matrices maintaining architectural characteristics of connective tissue.

A long-term invasion assay using fibrous connective tissue matrices was developed. The matrices were prepared by treating murine skin or human dura mater with 25 mM ammonium hydroxide containing proteinase inhibitors at 4 degrees C for 7 days. They could be maintained almost indefinitely without the degeneration and necrosis. Electron micrographs of them revealed the preservation of native collagen fibers, and sequential enzyme digestion showed the presence of glycoprotein in the matrices. Local dissolution of extracellular matrix by cultured human rectal adenocarcinoma cell line, RCM-1, was observed morphologically and confirmed by a quantitative assay using radiolabeled matrices. The destruction of extracellular matrix occurred associated with membrane vesicle-shedding from the cells. Both the advantages and disadvantages of this assay were discussed.

Animals↗
PubMed1988

Multiple connective tissue nevi.

Connective tissue nevi are uncommon, and rarely suspected clinically because of their diverse morphologic presentations. Histologically, we define connective tissue nevi as discrete areas within the papillary or recticular dermis where a clear predominance or depletion of collagen, elastin, or glycosaminoglycans may be found. We report a case of multiple connective tissue nevi with a predominance of dermal collagen deposition, without extracutaneous findings and no family history of connective tissue nevi. These lesions can thus be classified as being of the eruptive collagenoma type.

Adult↗
PubMed1985

Connective tissue activation: stimulation of glucose transport by connective tissue activating peptide III.

Connective tissue activating peptide III (CTAP III), a human platelet derived growth factor, induced marked stimulation of 2-deoxy[14C]glucose (2dG) uptake in cultures of human synovial cells, chondrocytes, and dermal fibroblasts. Cytochalasin B (2 X 10(-5) M) blocked the mediator-induced increase in 2dG uptake; phlorhizin (8 X 10(-4) M) partially inhibited this process. When cells were exposed to CTAP III (4 X 10(-6) M) for 30 min prior to uptake assay, 2dG uptake was stimulated by 30-110%; greater stimulation (400-800%) occurred following 17-40-h preincubation with the mediator. A 17-h exposure to CTAP III similarly stimulated 3-O-methylglucose uptake by over 400%, suggesting that CTAP III stimulated 2dG uptake is mediated via changes in hexose transport. Cycloheximide clearly prevented the 17-h effects of CTAP III on 2dG uptake. Insulin (3 X 10(-6) M) stimulated 2dG uptake 40-70% after 30-min preincubation with hormone; little effect was seen after 17-h preincubation. These data suggest that CTAP III stimulates glucose transport shortly after addition to target cells; the major stimulation observed after a 17-h incubation is consistent with the synthesis of new glucose transport protein.

Biological Transport, Active↗
PubMed2005

[Expression and implication of tissue transglutaminase and connective tissue growth factor at fibrotic tubulointerstitium in kidneys from UUO rats].

OBJECTIVE: To observe the expression and co-locolization of tissue transglutaminase (tTG) and connective tissue growth factor (CTGF) in kidneys from rats with tubulointerstitial fibrosis. METHODS: The animal models of unilateral ureteral obstruction (UUO) were used. The rats were randomly divided into the sham-operation group (n=5), the UUO group (n=6), and the Enalapril-treated UUO group (n=6). All the rats were sacrificed on day 9, the kidneys were collected, and renal interstitial fibrosis was examined by periodic acid-Schiff (PAS) staining. The expression and localization of tTG, CTGF, and Fibronectin( FN) in the obstructed kidneys were detected by immunohistochemistry staining. The protein levels of tTG and CTGF of the whole kidney homogenates were determined by Western blot analysis. RESULTS: Weak signals of tTG, CTGF, and FN-positive immunostaining were observed in renal tubular cells and tubulointerstitium, and very rare positive signals were seen in the glomeruli in the sham-operation group. However, much intensive signals of tTG, CTGF, and FN-positive immunostaining were observed in renal tubular cells and tubulointerstitium in the UUO group, and the intensity of signals were decreased in the Enalapril-treated UUO group. Co-localization of tTG and CTGF immunoreactivity were observed in tubulointerstitium in the UUO group. The levels of tTG and CTGF protein analyzed by Western blotting were increased remarkably in the UUO group compared with the sham-operation group, and a significant reduction of tTG and CTGF protein levels were presented in the Enalapril-treated UUO group compared with the UUO group. The levels of tTG protein had positive correlation with the levels of CTGF protein (r=0.683, P<0.05), and with the semi-quantitative levels of FN expression (r=0.737, P<0.05). CONCLUSION: Both tTG and CTGF may play a concordant role in the pathogenesis of renal tubulointerstitial fibrosis,and Enalapril may suppress the development of fibrosis partially via down-regulation of tTG and CTGF expression.

Animals↗