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PubMed1994

Control of cytoskeletal mechanics by extracellular matrix, cell shape, and mechanical tension.

We have investigated how extracellular matrix (ECM) alters the mechanical properties of the cytoskeleton (CSK). Mechanical stresses were applied to integrin receptors on the apical surfaces of adherent endothelial cells using RGD-coated ferromagnetic microbeads (5.5-microns diameter) in conjunction with a magnetic twisting device. Increasing the number of basal cell-ECM contacts by raising the fibronectin (FN) coating density from 10 to 500 ng/cm2 promoted cell spreading by fivefold and increased CSK stiffness, apparent viscosity, and permanent deformation all by more than twofold, as measured in response to maximal stress (40 dyne/cm2). When the applied stress was increased from 7 to 40 dyne/cm2, the stiffness and apparent viscosity of the CSK increased in parallel, although cell shape, ECM contacts, nor permanent deformation was altered. Application of the same stresses over a lower number ECM contacts using smaller beads (1.4-microns diameter) resulted in decreased CSK stiffness and apparent viscosity, confirming that this technique probes into the depth of the CSK and not just the cortical membrane. When magnetic measurements were carried out using cells whose membranes were disrupted and ATP stores depleted using saponin, CSK stiffness and apparent viscosity were found to rise by approximately 20%, whereas permanent deformation decreased by more than half. Addition of ATP (250 microM) under conditions that promote CSK tension generation in membrane-permeabilized cells resulted in decreases in CSK stiffness and apparent viscosity that could be detected within 2 min after ATP addition, before any measurable change in cell size. Permanent deformation only decreased after 20 min, once the CSK lattice had physically contracted. Importantly, regardless of cell shape or membrane continuity, CSK stiffness increased in direct proportion to the applied stress, as predicted by tensegrity (tensional integrity) cell models. These results suggest that the effects of ECM on CSK mechanics are not due to changes in osmotic or hydrostatic pressures. Rather, ECM alters CSKstiffness and apparent viscosity by binding integrins, promoting formation of molecular links with the CSK, transmitting mechanical stresses across these linkages, and inducing structural rearrangements within a continuous, tensionally integrated CSK lattice. In contrast, permanent deformation in the CSK appears to be more tightly coupled to cell extension and depends on both passive plasticity and dynamic remodeling events.

Animals↗
PubMed2007

Ageing of the conduit arteries.

Conduit arteries become stiffer with age due to alterations in their morphology and the composition of the their major structural proteins, elastin and collagen. The elastic lamellae undergo fragmentation and thinning, leading to ectasia and a gradual transfer of mechanical load to collagen, which is 100-1000 times stiffer than elastin. Possible causes of this fragmentation are mechanical (fatigue failure) or enzymatic (driven by matrix metallo proteinases (MMP) activity), both of which may have genetic or environmental origins (fetal programming). Furthermore, the remaining elastin itself becomes stiffer, owing to calcification and the formation of cross-links due to advanced glycation end-products (AGEs), a process that affects collagen even more strongly. These changes are accelerated in the presence of disease such as hypertension, diabetes and uraemia and may be exacerbated locally by atherosclerosis. Raised MMP activity, calcification and impaired endothelial function are also associated with a high level of plasma homocysteine, which itself increases with age. Impaired endothelial function leads to increased resting vascular smooth muscle tone and further increases in vascular stiffness and mean and/or pulse pressure. The effect of increased stiffness, whatever its underlying causes, is to reduce the reservoir/buffering function of the conduit arteries near the heart and to increase pulse wave velocity, both of which increase systolic and pulse pressure. These determine the peak load on the heart and the vascular system as a whole, the breakdown of which, like that of any machine, depends more on the maximum loads they must bear than on their average. Reversing or stabilising the increased arterial stiffness associated with age and disease by targeting any or all of its causes provides a number of promising new approaches to the treatment of systolic hypertension and its sequelae, the main causes of mortality and morbidity in the developed world.

Aging↗
PubMed2002

Correlation of cartilage oligomeric matrix protein (COMP) levels in equine tendon with mechanical properties: a proposed role for COMP in determining function-specific mechanical characteristics of locomotor tendons.

Over-strain injury of the superficial digital flexor tendon (SDFT) is a common injury in the horse. Tendon appears to adapt to loads placed on it during development, but fatigue damage accumulates after skeletal maturity, which is inadequately repaired and predisposes to clinical tendinitis. In any population of horses, there is a wide variation in SDFT mechanical properties. A noncollagenous protein, cartilage oligomeric matrix protein (COMP), is particularly abundant during growth in the equine SDFT and has been proposed to have an organisational role in the formation of collagenous matrices. This study aimed to determine whether COMP levels were correlated to mechanical properties at skeletal maturity. Tendons from 2 groups of 12 horses were analysed: Group 1 horses with restricted age, 2 years +/- 2 months, showed a significant correlation between both ultimate tensile stress modulus of elasticity and stiffness and COMP, while Group 2 mature horses with varying age did not, because of age- and exercise-induced loss of COMP. These data supports the hypothesis that COMP is an important mediator in the growth of tendon. This data would suggest that the identification of low COMP levels in tendon during growth would indicate horses prone to tendon injury and methods of promoting COMP synthesis during growth would potentially improve tendon quality and reduce the risk of subsequent tendinitis.

Age Factors↗
PubMed2001

Numerical modeling of coupled variably saturated fluid flow and reactive transport with fast and slow chemical reactions.

The couplings among chemical reaction rates, advective and diffusive transport in fractured media or soils, and changes in hydraulic properties due to precipitation and dissolution within fractures and in rock matrix are important for both nuclear waste disposal and remediation of contaminated sites. This paper describes the development and application of LEHGC2.0, a mechanistically based numerical model for simulation of coupled fluid flow and reactive chemical transport, including both fast and slow reactions in variably saturated media. Theoretical bases and numerical implementations are summarized, and two example problems are demonstrated. The first example deals with the effect of precipitation/dissolution on fluid flow and matrix diffusion in a two-dimensional fractured media. Because of the precipitation and decreased diffusion of solute from the fracture into the matrix, retardation in the fractured medium is not as large as the case wherein interactions between chemical reactions and transport are not considered. The second example focuses on a complicated but realistic advective-dispersive-reactive transport problem. This example exemplifies the need for innovative numerical algorithms to solve problems involving stiff geochemical reactions.

Diffusion↗
PubMed2001

Predictive rheological models for the consolidation behaviour of articular cartilage under static loading.

This paper evaluates an existing rheological model of articular cartilage and explores the representative capacity of other phenomenological models of the tissue's matrix within the framework of mechanical consolidation. A unique feature is the introduction of a swelling element in tandem with 'fluid-filled' hyperelastic rheological elements to predict the transient load-induced behaviour of the tissue and evaluate the role of swelling in determining its load-carriage mechanism. The rheological models proposed have been used to predict the dependence of the one-dimensional consolidation response of the articular cartilage matrix, and the results obtained have been compared with published experimental results. This comparison demonstrates that the hydrostatic excess pore pressure, especially in the initial stages of deformation cannot be predicted without an adequate representation of swelling and its non-linear interaction with mechanical governing parameters such as permeability and stiffness.

Australia↗
PubMed1976

The features of sperm maturation in the epididymis of a marsupial, the brushtailed possum Trichosurus vulpecula.

Possum spermatozoa undergo a distinctive process of maturation in the epididymis, as shown by change in the properties of the sperm surface, by modification of their morphology and by their increasing capacity for progressive motility. Modification of the sperm surface over the head and tail is demonstrated by the different affinities of sperm from successive regions of the epididymis for FITC-conjugated wheat germ agglutinin and concanavalin A, and for cationic ferric oxide colloidal particles. Changes in sperm head morphology are caused by (1) a dramatic reshaping and consolidation of the acrosome in which excess plasma membrane overlying it is sloughed as a cluster of vesicles, (2) a reorientation of the nucleus almost parallel to the axis of the tail and (3) distal movement of the droplet from its initial envelopment of the nucleus to an eccentric position on the anterior segment of the midpiece. Spermatozoa released from the testis and caput epididymidis are essentially immotile or exhibit only lazy uncoordinated movements, whereas many from the corpus and most from the more distal regions of the epididymis display an energetic, progressive motility imparted by a rapid and stiff tail beat of narrow arc. This maturation of the capacity for motility is accompanied by an enhanced stability of the dense fibers and sheath, which became more resistant to the disruptive action of SDS and DTT, and by changes in the ultrastructure of the sperm tail. These include modification of the matrix of the mitochondria and also an unusual differentation of the midpiece into two distinct segments. The anterior segment is defined by profuse peri-mitochondrial stacks of membranes which developed as spermatozoa pass through the epididymis. These membranes, although prominent in mature spermatozoa fixed in situ, appear sparse and disorganised in spermatozoa fixed after 15 to 30 minutes of active motility in physiological medium, suggesting their possible utilisation in motile spermatozoa. The posterior segment is characterised by a thick peri-mitochondrial cytoplasmic sleeve, by spirally arranged parallel fibrous bands immediately beneath the plasma membrane and, subsequently, as spermatozoa pass into the lower corpus epididymidis, by rows of flask-shaped surface invaginations which develop between the spiral bands. Despite broad similarities in the features of sperm maturation in this marsupial and in eutherian mammals, there are distinct differencesin the structural organisation of their spermatozoa, particularly in the pserm head. Until more is known of the details of fertilisation in marsupials the significance of these differences will remain unclear.

Agglutinins↗
PubMed2001

Biosynthetic response and mechanical properties of articular cartilage after injurious compression.

Traumatic joint injury is known to produce osteoarthritic degeneration of articular cartilage. To study the effects of injurious compression on the degradation and repair of cartilage in vitro, we developed a model that allows strain and strain rate-controlled loading of cartilage explants. The influence of strain rate on both cartilage matrix biosynthesis and mechanical properties was assessed after single injurious compressions. Loading with a strain rate of 0.01 s(-1) to a final strain of 50% resulted in no measured effect on the cells or on the extracellular matrix, although peak stresses reached levels of about 12 MPa. However, compression with strain rates of 0.1 and 1 s(-1) caused peak stresses of approximately 18 and 24 MPa, respectively, and resulted in significant decreases in both proteoglycan and total protein biosynthesis. The mechanical properties of the explants (compressive and shear stiffness) were also reduced with increasing strain rate. Additionally, cell viability decreased with increasing strain rate, and the remaining viable cells lost their ability to exhibit an increase in biosynthesis in response to low-amplitude dynamic mechanical stimulation. This latter decrease in reparative response was most dramatic in the tissue compressed at the highest strain rates. We conclude that strain rate (like peak stress or strain) is an important parameter in defining mechanical injury, and that cartilage injuriously compressed at high strain rates can lose its characteristic anabolic response to low-amplitude cyclic mechanical loading.

Animals↗
PubMed2005

Direct measurement of osmotic pressure of glycosaminoglycan solutions by membrane osmometry at room temperature.

Articular cartilage is a hydrated soft tissue composed of negatively charged proteoglycans fixed within a collagen matrix. This charge gradient causes the tissue to imbibe water and swell, creating a net osmotic pressure that enhances the tissue's ability to bear load. In this study we designed and utilized an apparatus for directly measuring the osmotic pressure of chondroitin sulfate, the primary glycosaminoglycan found in articular cartilage, in solution with varying bathing ionic strength (0.015 M, 0.15 M, 0.5 M, 1 M, and 2 M NaCl) at room temperature. The osmotic pressure (pi) was found to increase nonlinearly with increasing chondroitin sulfate concentration and decreasing NaCl ionic bath environment. Above 1 M NaCl, pi changes negligibly with further increases in salt concentration, suggesting that Donnan osmotic pressure is negligible above this threshold, and the resulting pressure is attributed to configurational entropy. Results of the current study were also used to estimate the contribution of osmotic pressure to the stiffness of cartilage based on theoretical and experimental considerations. Our findings indicate that the osmotic pressure resulting from configurational entropy is much smaller in cartilage (based on an earlier study on bovine articular cartilage) than in free solution. The rate of change of osmotic pressure with compressive strain is found to contribute approximately one-third of the compressive modulus (H(A)(eff)) of cartilage (Pi approximately H(A)(eff)/3), with the balance contributed by the intrinsic structural modulus of the solid matrix (i.e., H(A) approximately 2H(A)(eff)/3). A strong dependence of this intrinsic modulus on salt concentration was found; therefore, it appears that proteoglycans contribute structurally to the magnitude of H(A), in a manner independent of osmotic pressure.

Animals↗
PubMed2002

The association between venous structural alterations and biomechanical weakness in patients with abdominal aortic aneurysms.

OBJECTIVE: Abdominal aortic aneurysms (AAAs) are associated with generalized arterial dilation, torturosity, and altered matrix composition, which suggests a generalized systemic weakness throughout the entire vasculature. The aim of this study was to determine whether this phenomenon was present in the venous tissue of patients with AAA. METHODS: A segment of inferior mesenteric vein was harvested from patients who underwent aneurysm repair (n = 11) or colectomy for diverticulosis (n = 11; control). Matrix composition of the vessel was determined with stereology, and dimensions were measured with a computerized image analysis system. Stress-strain measurements were calculated with elongation of inferior mesenteric vein tissue with a tensile-testing machine. RESULTS: Histologic examination results showed fragmentation of elastin fibers within the medial layer of venous tissue obtained from patients with AAA. The medial elastin content in tissue from patients with aneurysms was 19.4%, compared with 26.8% in the control group (P =.018). Mechanical test results revealed a significant reduction in the tensile strength from 2.885 MPa in the control group to 1.405 MPa in the AAA group (P =.007). This reduction corresponded with a significant reduction of 59% in the stiffness of the vessel, with the mean Young's modulus of elasticity in the AAA group being 2.72 MPa, compared with 5.361 MPa in the control group (P =.0005). CONCLUSION: Reduction in tensile strength and stiffness in venous tissue from patients with AAA was associated with disruption and reduction of the elastin content of the vein wall. These changes are analogous to those observed in the arterial aneurysmal wall and confirm the systemic nature of this disorder.

Aged↗
PubMedDate not supplied

Functional bone engineering using ex vivo gene therapy and topology-optimized, biodegradable polymer composite scaffolds.

Bone tissue engineering could provide an alternative to conventional treatments for fracture nonunion, spinal fusion, joint replacement, and pathological loss of bone. However, this approach will require a biocompatible matrix to allow progenitor cell delivery and support tissue invasion. The construct must also support physiological loads as it degrades to allow the regenerated tissue to bear an increasing load. To meet these complex requirements, we have employed topology-optimized design and solid free-form fabrication to manufacture biodegradable poly(propylene fumarate)/beta-tricalcium phosphate composites. These scaffolds were seeded with primary human fibroblasts transduced with an adenovirus expressing bone morphogenetic protein-7 and implanted subcutaneously in mice. Specimens were evaluated by microcomputed tomography, compressive testing, and histological staining. New bone was localized on the scaffold surface and closely followed its designed contours. Furthermore, the total stiffness of the constructs was retained for up to 12 weeks after implantation, as scaffold degradation and tissue invasion took place.

Adenoviridae↗
PubMed2004

Synthesis of immune modulators by smooth muscles.

The primary function of smooth muscle cells is to contract and alter the stiffness or diameter of hollow organs such as blood vessels, the airways and the gastrointestinal and urogenital tracts. In addition to purely structural functions, smooth muscle cells may play important metabolic roles, particularly in various inflammatory responses. In cell culture, these cells have been shown to be metabolically dynamic, synthesizing and secreting extracellular matrix proteins, glycosaminoglycans and a wide variety of cell-cell signaling proteins, such as interleukins, chemokines and peptide growth factors. Secreted cell signaling proteins participate in the inflammatory response of smooth muscle-containing organs, and some can also stimulate smooth muscle migration, proliferation and contraction. The cellular signaling pathways controlling synthesis of these signaling proteins are similar to those used by cells mediating innate immunity and may contribute to pathogenesis of diverse diseases including atherosclerosis, asthma, inflammatory bowel diseases and preterm labor. Appreciating the role of smooth muscle cells in these diseases may lead to better understanding of the beneficial effects of anti-inflammatory drugs as well as identification of new targets for anti-inflammatory therapy.

Animals↗
PubMed2002

Does peripheral quantitative computed tomography ignore tissue density of cancellous bone?

The purpose of this work was to determine the capacity of peripheral quantitative computed tomography (pQCT) to accurately measure the true physical properties of vertebral cancellous bone samples and to predict their stiffness. pQCT bone mineral density (BMD) was first measured in ideal conditions. Ten cubic specimens of vertebral cancellous bone (10 x 10 x 10 mm) were washed with a water jet, defatted, and scanned in saline after elimination of air bubbles; thirteen slices were obtained. Seventy-one unprepared cylindrical samples were scanned in more realistic conditions, which allow further biomechanical testing. After extraction from the vertebral body, the samples were pushed into a plastic tube (no effort was made to remove the marrow or air bubbles), and only four slices were obtained to reduce the duration of scan. For the 81 samples, the true bone volume fraction (BV/TV, %), true apparent density (rho(app), g/cm(3)), and tissue density (rho(tiss), g/cm(3)) (an indicator of the degree of mineralization of the matrix) were then measured using Archimedes principle. rho(app) was closely correlated to BV/TV (r(2) = 0.97). rho(tiss) (1.58 +/- 0.08 g/cm(2)) was almost constant but had some influence on rho(app) (r(2) = 0.03, p < 0.001). The pQCT BMD predicted accurately rho(app) (r(2) = 0.96) and BV/TV (r(2) = 0.93) for the cylinders. For the cubes, in ideal conditions, the same correlations were even better (r(2) > 0.99, both). Analysis of covariance indicated no difference (p > 0.05) in the regressions due to preparation of the samples. The stiffness was better predicted by the true rho(app) (r(2) = 0.87) than by BV/TV (r(2) = 0.83), indicating that stiffness was influenced by small differences in the tissue density. Consequently, the correlation between pQCT BMD and stiffness was excellent (r(2) = 0.84). The fact that pQCT did not ignore this tissue density information compensated for the inaccuracies linked to realistic scanning conditions of the cylinder.

Adult↗
PubMed2000

Injurious mechanical compression of bovine articular cartilage induces chondrocyte apoptosis.

A bovine cartilage explant system was used to evaluate the effects of injurious compression on chondrocyte apoptosis and matrix biochemical and biomechanical properties within intact cartilage. Disks of newborn bovine articular cartilage were compressed in vitro to various peak stress levels and chondrocyte apoptotic cell death, tissue biomechanical properties, tissue swelling, glycosaminoglycan loss, and nitrite levels were quantified. Chondrocyte apoptosis occurred at peak stresses as low as 4.5 MPa and increased with peak stress in a dose-dependent manner. This increase in apoptosis was maximal by 24 h after the termination of the loading protocol. At high peak stresses (>20 MPa), greater than 50% of cells apoptosed. When measured in uniaxial confined compression, the equilibrium and dynamic stiffness of explants decreased with the severity of injurious load, although this trend was not significant until 24-MPa peak stress. In contrast, the equilibrium and dynamic stiffness measured in radially unconfined compression decreased significantly after injurious stresses of 12 and 7 MPa, respectively. Together, these results suggested that injurious compression caused a degradation of the collagen fibril network in the 7- to 12-MPa range. Consistent with this hypothesis, injurious compression caused a dose-dependent increase in tissue swelling, significant by 13-MPa peak stress. Glycosaminoglycans were also released from the cartilage in a dose-dependent manner, significant by 6- to 13-MPa peak stress. Nitrite levels were significantly increased above controls at 20-MPa peak stress. Together, these data suggest that injurious compression can stimulate cell death as well as a range of biomechanical and biochemical alterations to the matrix and, possibly, chondrocyte nitric oxide expression. Interestingly, chondrocyte programmed cell death appears to take place at stresses lower than those required to stimulate cartilage matrix degradation and biomechanical changes. While chondrocyte apoptosis may therefore be one of the earliest responses to tissue injury, it is currently unclear whether this initial cellular response subsequently drives cartilage matrix degradation and changes in the biomechanical properties of the tissue.

Animals↗
PubMed2004

Thermoreversible hydrogel scaffolds for articular cartilage engineering.

Articular cartilage has limited potential for repair. Current clinical treatments for articular cartilage damage often result in fibrocartilage and are associated with joint pain and stiffness. To address these concerns, researchers have turned to the engineering of cartilage grafts. Tissue engineering, an emerging field for the functional restoration of articular cartilage and other tissues, is based on the utilization of morphogens, scaffolds, and responding progenitor/stem cells. Because articular cartilage is a water-laden tissue and contains within its matrix hydrophilic proteoglycans, an engineered cartilage graft may be based on synthetic hydrogels to mimic these properties. To this end, we have developed a polymer system based on the hydrophilic copolymer poly(propylene fumarate-co-ethylene glycol) [P(PF-co-EG)]. Solutions of this polymer are liquid below 25 degrees C and gel above 35 degrees C, allowing an aqueous solution containing cells at room temperature to form a hydrogel with encapsulated cells at physiological body temperature. The objective of this work was to determine the effects of the hydrogel components on the phenotype of encapsulated chondrocytes. Bovine articular chondrocytes were used as an experimental model. Results demonstrated that the components required for hydrogel fabrication did not significantly reduce the proteoglycan synthesis of chondrocytes, a phenotypic marker of chondrocyte function. In addition, chondrocyte viability, proteoglycan synthesis, and type II collagen synthesis within P(PF-co-EG) hydrogels were investigated. The addition of bone morphogenetic protein-7 increased chondrocyte proliferation with the P(PF-co-EG) hydrogels, but did not increase proteoglycan synthesis by the chondrocytes. These results indicate that the temperature-responsive P(PF-co-EG) hydrogels are suitable for chondrocyte delivery for articular cartilage repair.

Animals↗
PubMed1994

Distribution of procollagen type III, collagen type VI and tenascin in oral submucous fibrosis (OSF).

The distribution of procollagen type III, collagen type VI and tenascin was studied in biopsy specimens from the buccal mucosa of 19 Indian women with confirmed oral submucous fibrosis (OSF) using the immunogold-silver staining technique. Immunohistochemistry revealed a loss of stainable procollagen type III and collagen type VI in the fibrotic zones of oral submucous fibrosis compared to normal oral mucosa. Tenascin was noted only very faintly at the subepithelial basement membrane. The present study showed that procollagen type III and collagen type VI in OSF were expressed in a specific pattern which allows a clear differentiation between fibrotic areas and adjacent apparently normal connective tissue stroma. Loss of procollagen type III, and therefore a probable predominance of collagen type I in collagen fiber bundles, and an almost complete loss of collagen type VI might explain the stiffness of the oral mucosa in patients with OSF. The immunohistochemical findings provided evidence that the process of fibrosis starts in the deeper subepithelial connective tissue stroma and not close to the subepithelial basement membrane. Further studies are required to determine whether OSF is due to increased or altered synthesis and deposition of extracellular matrix proteins, altered fibrolysis or both.

Adult↗
PubMedDate not supplied

Autologous chondrocyte transplantation. Biomechanics and long-term durability.

We evaluated the durability of autologous chondrocyte transplantation grafts in 61 patients treated for isolated cartilage defects on the femoral condyle or the patella and followed up for a mean of 7.4 years (range, 5 to 11). Durability was determined by comparing the clinical status at the long-term follow-up with that found 2 years after the transplantation. After 2 years, 50 of the 61 patients had good or excellent clinical results, and 51 of 61 had good or excellent results at 5 to 11 years later. Grafted areas from 11 of the patients were evaluated with an electromechanical indentation probe during a second-look arthroscopy procedure (mean follow-up, 54.3 months; range, 33 to 84); stiffness measurements were 90% or more of those of normal cartilage in eight patients. Eight of twelve 2-mm biopsy samples taken from these patients showed hyaline characteristics with safranin O staining and a homogeneous appearance in polarized light. Three fibrous and eight hyaline biopsy specimens stained positive to aggrecan and to cartilage oligomeric matrix protein. Hyaline-like specimens stained positive for type II collagen, and fibrous, for type I collagen. Autologous chondrocyte transplantation for the treatment of articular cartilage injuries has a durable outcome for as long as 11 years.

Adolescent↗
PubMed2001

Aceclofenac: a reappraisal of its use in the management of pain and rheumatic disease.

UNLABELLED: Aceclofenac is an orally administered phenylacetic acid derivative with effects on a variety of inflammatory mediators. Through its analgesic and anti-inflammatory properties, aceclofenac provides symptomatic relief in a variety of painful conditions. In patients with osteoarthritis of the knee, the drug decreases pain, reduces disease severity and improves the functional capacity of the knee to a similar extent to diclofenac, piroxicam and naproxen. Aceclofenac reduces joint inflammation, pain intensity and the duration of morning stiffness in patients with rheumatoid arthritis, and is similar in efficacy to ketoprofen, diclofenac, indomethacin and tenoxicam in these patients. The duration of morning stiffness and pain intensity are reduced, and spinal mobility improved, by aceclofenac in patients with ankylosing spondylitis, with improvements being similar to those observed with indomethacin, naproxen or tenoxicam. Aceclofenac is also effective in other painful conditions (e.g. dental and gynaecological). In contrast to some other NSAIDs, aceclofenac has shown stimulatory effects on cartilage matrix synthesis. Aceclofenac is well tolerated, with most adverse events being minor and reversible, and affecting mainly the GI system. Although the incidence of GI adverse events with aceclofenac was similar to those of comparator NSAIDs in individual clinical trials, withdrawal rates due to these events were significantly lower with aceclofenac than with ketoprofen and tenoxicam. Superior overall and/or GI tolerability of the drug relative to other NSAIDs has been indicated by a nonrandomised comparison with sustained release diclofenac in 10,142 patients, a meta-analysis of 13 comparisons with diclofenac, naproxen, piroxicam, indomethacin, tenoxicam or ketoprofen in 3574 patients, and preliminary details of a comparison with 10 other NSAIDs in 142,776 patients. Further analysis of the above meta-analytical data has indicated that costs incurred as a result of adverse event management are lower with aceclofenac than with a range of comparator NSAIDs. CONCLUSIONS: Trials of 2 to 6 months' duration have shown aceclofenac to be an effective agent in the management of pain and rheumatic disease. Data from in vitro studies indicate properties of particular interest with respect to cartilage matrix effects and selectivity for cyclo-oxygenase-2. Aceclofenac is well tolerated, with encouraging reports of improved general and GI tolerability relative to other NSAIDs from a meta-analysis of double-blind trials and from large nonblind studies.

Animals↗
PubMed2004

Fine tuning of growth factor signals depends on fibrillin microfibril networks.

Growth factors, potent regulators of cell differentiation, tissue morphogenesis, tissue homeostasis, and cellular response to injury, reside in the extracellular matrix. Genetic evidence in humans and mice as well as biochemical data implicate fibrillins and LTBPs in the extracellular control of TGFbeta and BMP signaling. Fibrillins and LTBPs form tissue-specific and temporally regulated microfibril networks. In the developing embryo, three fibrillins and four LTBPs contribute molecular heterogeneity to microfibril networks, and provide different templates upon which TGFbeta-related growth factors can be positioned. By accommodating this molecular heterogeneity, microfibril architecture can orchestrate a variety of different signals in very specific tissue locations. Human fibrillinopathies display a broad phenotypic spectrum from tall to short stature, from hypermobile joints to joint contractures and stiffness, and from severe to mild or no cardiovascular manifestations. A spectrum of growth factor dysregulation may be caused by differential effects of mutations in fibrillins on microfibril architecture, thus altering appropriate targeting or positioning of growth factors within microfibril networks. Growth factor dysregulation may help to explain the broad phenotypic spectrum of the fibrillinopathies.

Amino Acid Sequence↗