锌转运蛋白ZIP8 在骨关节炎中的表达及其机制研究

目的:探讨锌转运蛋白ZIP8在骨关节炎患者中的表达及其对软骨细胞生长及基质金属蛋白酶(MMPs)表达的影响。方法:收集20例骨关节炎患者(OA组)和20例非骨关节炎患者(对照组)血清和软骨组织;采用原子吸收分光光度计测定患者血清和软骨组织中锌离子的表达水平;MTT方法检测软骨细胞的生长活力;采用小RNA干扰沉默ZIP8基因的表达;实时荧光定量PCR方法检测ZIP8及金属基质蛋白酶MMP3、MMP9、MMP12和MMP13等基因的m RNA表达水平;蛋白免疫印迹检测ZIP8及MMP3、MMP9、MMP12和MMP13等蛋白的表达水平。结果:OA组的血清和软骨组织中的锌离子浓度明显高于对照组(P0.01)。OA组软骨组织中ZIP8的m RNA(P0.05)和蛋白(P0.01)表达水平显著高于对照组。ZIP8小RNA干扰片段可以有效的沉默ZIP的基因表达(P0.01);沉默ZIP8的表达促进骨关节炎患者来源的软骨细胞的生长(P0.05),并且降低基质金属蛋白酶包括MMP3,MMP9,MMP12和MMP13的表达水平(P0.05)。结论:ZIP8与骨关节炎密切相关,沉默ZIP8的表达可以提高软骨细胞的生长活力,并且抑制基质金属蛋白酶的表达,为骨关节炎的治疗提供了新的靶点。     

Spherical classification of wavelet transformed EMG intensity patterns

Electromyograms of different muscles can be submitted to a wavelet-transform and arranged in a Multi-Muscle Pattern (MMP). The MMP represents the intensity of the EMG signals of a number of muscles simultaneously in time/frequency space. As previously shown, the MMPs can be represented by points in an Euclidian vector space that was called pattern space. The variability of the MMPs is represented by the distribution of the scattered points in pattern space. The purpose of this study was to investigate the distribution of the points and use the properties of the distribution to classify MMPs. The first task was to test whether the points representing a group of MMPs were located between the inner and outer boundary of a sphere-like domain in whitened pattern space as theoretically predicted. The mean of these points and thus of the MMPs is represented by a point at the center of the sphere. The hypothesis was that the spheres representing points of the MMPs of barefoot and shod runners were sufficiently separated and distinguishable in pattern space to allow classification of the runners according to their shod condition. The results confirmed the hypothesis and revealed that the recognition rate was over 80%. One can conclude and generalize that the points representing MMPs recorded for a certain condition reside between the inner and outer boundary of the sphere. The classification based on the spherical feature represents a much better discrimination than one based on the distance from the mean.     

Identification and classification of involuntary leg muscle contractions in electromyographic records from individuals with spinal cord injury

Involuntary muscle contractions (spasms) are common after human spinal cord injury (SCI). Our aim was to compare how well two raters independently identified and classified different types of spasms in the same electromyographic records (EMG) using predefined rules. Muscle spasms were identified by the presence, timing and pattern of EMG recorded from paralyzed leg muscles of four subjects with chronic cervical SCI. Spasms were classified as one of five types: unit, tonic, clonus, myoclonus, mixed. In 48 h of data, both raters marked the same spasms most of the time. More variability in the total spasm count arose from differences between muscles (84%; within subjects) than differences between subjects (6.5%) or raters (2.6%). Agreement on spasm classification was high (89%). Differences in spasm count, and classification largely occurred when EMG was marked as a single spasm by one rater but split into multiple spasms by the other rater. EMG provides objective measurements of spasm number and type in contrast to the self-reported spasm counts that are often used to make clinical decisions about spasm management. Data on inter-rater agreement and discrepancies on muscle spasm analysis can both drive the design and evaluation of software to automate spasm identification and classification.     

Effects of ceramide on apoptosis, proteoglycan degradation, and matrix metalloproteinase expression in rabbit articular cartilage

Cartilage loss in osteoarthritis is characterized by matrix degradation and chondrocyte death. The lipid messenger ceramide is implicated in signal transduction of the catabolic cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), as well as in apoptosis. The aim of this study was to examine the in vitro effects of ceramide on proteoglycan degradation, matrix-metalloproteinase (MMP) expression and activity, and chondrocyte apoptosis in rabbit articular cartilage. Cell-permeant ceramide C(2) stimulated proteoglycan degradation in cartilage explants starting from 3 x 10(-5) M, with 100% increase at the dose of 10(-4) M. This effect was probably due to MMPs since it was blocked by the MMP inhibitor batimastat. Furthermore, in isolated chondrocytes, C(2) stimulated the expression of MMP-1, 3, and 13 at the mRNA level, MMP activity, and MMP-3 production. Ceramide also caused chondrocyte apoptosis at doses ranging from 10(-5) to 10(-4) M. This study supports the hypothesis that ceramide might play a mediatory role in both matrix degradation and apoptosis in processes of cartilage loss such as those observed in osteoarthritis.     

A novel approach to measure the contribution of matrix metalloproteinase in the overall net proteolytic activity present in synovial fluids of patients with arthritis

Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis patients correlated positively with the number of infiltrated leukocytes and the serum level of C-reactive protein. No such correlations were found in osteoarthritis patients. Members of the MMP family contributed significantly to the proteolytic activity found in SF. Small-molecular-weight MMP inhibitors were indeed effective for inhibiting proteolytic activity in SF, but their effectiveness varied greatly among patients. Interestingly, the contribution of MMPs decreased in patients with very high proteolytic activity, and this was due both to a molar excess of tissue inhibitor of MMP-1 and to an increased contribution of other proteolytic enzymes. These results emphasize the diversity of the MMPs involved in arthritis and, from a clinical perspective, suggest an interesting alternative for testing the potential of new protease inhibitors for the treatment of arthritis.     

Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease.

Patients with peripheral arterial disease (PAD) have abnormalities of carnitine metabolism that may contribute to their functional impairment. To test the hypothesis that muscle acylcarnitine generation (intermediates in oxidative metabolism) in patients with PAD provides a marker of the muscle dysfunction, 10 patients with unilateral PAD and 6 age-matched control subjects were studied at rest, and the patients were studied during exercise. At rest, biopsies of the gastrocnemius muscle in the patients' nonsymptomatic leg revealed a normal carnitine pool and lactate content compared with control subjects. In contrast, the patients' diseased leg had higher contents of lactate and long-chain acylcarnitines than controls. The muscle short-chain acylcarnitine content in the patients' diseased leg at rest was inversely correlated with peak exercise performance (r = -0.75, P less than 0.05). With graded treadmill exercise, only patients who exceeded their individual lactate threshold had an increase in muscle short-chain acylcarnitine content in the nonsymptomatic leg, which was identical to the muscle carnitine response in normal subjects. In the patients' diseased leg, muscle short-chain acylcarnitine content increased with exercise from 440 +/- 130 to 900 +/- 200 (SE) nmol/g (P less than 0.05). In contrast to the nonsymptomatic leg, there was no increase in muscle lactate content in the diseased leg with exercise, and the change in muscle carnitine metabolism was correlated with exercise duration (r = 0.82, P less than 0.01) and not with the lactate threshold. We conclude that energy metabolism in ischemic muscle of patients with PAD is characterized by the accumulation of acylcarnitines.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated Atherosclerosis-Related Gene Expression,Monocyte Activation and Microparticle-Release Are Related to Increased Lipoprotein-Associated Oxidative Stress in Familial Hypercholesterolemia

Objective

Animal and in vitro studies have suggested that hypercholesterolemia and increased oxidative stress predisposes to monocyte activation and enhanced accumulation of oxidized LDL cholesterol (oxLDL-C) through a CD36-dependent mechanism. The aim of this study was to investigate the hypothesis that elevated oxLDL-C induce proinflammatory monocytes and increased release of monocyte-derived microparticles (MMPs), as well as up-regulation of CD36, chemokine receptors and proinflammatory factors through CD36-dependent pathways and that this is associated with accelerated atherosclerosis in subjects with heterozygous familial hypercholesterolemia (FH), in particular in the presence of Achilles tendon xanthomas (ATX).

Approach and Results

We studied thirty FH subjects with and without ATX and twenty-three healthy control subjects. Intima-media thickness (IMT) and Achilles tendon (AT) thickness were measured by ultrasonography. Monocyte classification and MMP analysis were performed by flow cytometry. Monocyte expression of genes involved in atherosclerosis was determined by quantitative PCR. IMT and oxLDL-C were increased in FH subjects, especially in the presence of ATX. In addition, FH subjects had elevated proportions of intermediate CD14++CD16+ monocytes and higher circulating MMP levels. Stepwise linear regression identified oxLDL-C, gender and intermediate monocytes as predictors of MMPs. Monocyte expression of pro-atherogenic and pro-inflammatory genes regulated by oxLDL-C-CD36 interaction was increased in FH, especially in ATX+ subjects. Monocyte chemokine receptor CX₃CR1 was identified as an independent contributor to IMT.

Conclusions

Our data support that lipoprotein-associated oxidative stress is involved in accelerated atherosclerosis in FH, particularly in the presence of ATX, by inducing pro-inflammatory monocytes and increased release of MMPs along with elevated monocyte expression of oxLDL-C-induced atherosclerosis-related genes.     

Regeneration of Soft Tissues Is Promoted by MMP1 Treatment after Digit Amputation in Mice

The ratio of matrix metalloproteinases (MMPs) to the tissue inhibitors of metalloproteinases (TIMPs) in wounded tissues strictly control the protease activity of MMPs, and therefore regulate the progress of wound closure, tissue regeneration and scar formation. Some amphibians (i.e. axolotl/newt) demonstrate complete regeneration of missing or wounded digits and even limbs; MMPs play a critical role during amphibian regeneration. Conversely, mammalian wound healing re-establishes tissue integrity, but at the expense of scar tissue formation. The differences between amphibian regeneration and mammalian wound healing can be attributed to the greater ratio of MMPs to TIMPs in amphibian tissue. Previous studies have demonstrated the ability of MMP1 to effectively promote skeletal muscle regeneration by favoring extracellular matrix (ECM) remodeling to enhance cell proliferation and migration. In this study, MMP1 was administered to the digits amputated at the mid-second phalanx of adult mice to observe its effect on digit regeneration. Results indicated that the regeneration of soft tissue and the rate of wound closure were significantly improved by MMP1 administration, but the elongation of the skeletal tissue was insignificantly affected. During digit regeneration, more mutipotent progenitor cells, capillary vasculature and neuromuscular-related tissues were observed in MMP1 treated tissues; moreover, there was less fibrotic tissue formed in treated digits. In summary, MMP1 was found to be effective in promoting wound healing in amputated digits of adult mice.     

Matrix metalloproteinases (MMPs) are required for wound closure and healing during larval leg regeneration in the flour beetle,Tribolium castaneum

Regenerative abilities are found ubiquitously among many metazoan taxa. To compare mechanisms underlying the initial stages of limb regeneration between insects and vertebrates, the roles of matrix metalloproteinases (MMPs) and fibroblast growth factor (FGF) signaling were investigated in the red flour beetle, Tribolium castaneum. RNA interference-mediated knockdown of MMP2 expression delayed wound healing and subsequent leg regeneration. Additionally, pairwise knockdown of MMP1/2 and MMP2/3, but not MMP1/3, resulted in inhibition of wound closure. Wound healing on the dorsal epidermis after injury was also delayed when MMPs were silenced. Our findings show that functionally redundant MMPs play key roles during limb regeneration and wound healing in Tribolium. This MMP-mediated wound healing is necessary for the subsequent formation of a blastema. In contrast, silencing of FGF receptor did not interfere with the initial stages of leg regeneration despite the alterations in tanning of the cuticle. Thus, insects and vertebrates appear to employ similar developmental processes for the initial stages of wound closure during limb regeneration, while the role of FGF in limb regeneration appears to be unique to vertebrates.     

Computational sequence analysis of matrix metalloproteinases

Matrix metalloproteinases (MMP) play a cardinal role in the breakdown of extracellular matrix involved in a variety of biological and pathological processes. Research on MMPs has classified and characterized these enzymes according to their matrix substrate specificity, gene and protein domain structure, and regulation of activity and expression. However, the discovery of new MMPs has introduced a need for a more comprehensive and systematic method of classification and quantitative comparison of known and newly discovered members. This study compiles a sequence alignment, constructs a dendrogram, and calculates physical data and homology percentage assignments in order to obtain further insight into MMP structure-function relationships. Thorough analysis of MMP primary sequence domains, physical data patterns, and statistical analysis of sequence homology yields higher resolution in the similarities and differences that group MMP members.     

MMP proteolysis of the human extracellular matrix protein aggrecan is mainly a process of normal turnover

Although it has been shown that aggrecanases are involved in aggrecan degradation, the role of MMP (matrix metalloproteinase) aggrecanolysis is less well studied. To investigate MMP proteolysis of human aggrecan, in the present study we used neoepitope antibodies against MMP cleavage sites and Western blot analysis to identify MMP-generated fragments in normal and OA (osteoarthritis/osteoarthritic) cartilage, and in normal, knee injury and OA and SF (synovial fluid) samples. MMP-3 in vitro digestion showed that aggrecan contains six MMP cleavage sites, in the IGD (interglobular domain), the KS (keratan sulfate) region, the border between the KS region and CS (chondroitin sulfate) region 1, the CS1 region, and the border between the CS2 and the G3 domain, and kinetic studies showed a specific order of digestion where the cleavage between CS2 and the G3 domain was the most preferred. In vivo studies showed that OA cartilage contained (per dry weight) 3.4-fold more MMP-generated FFGV fragments compared with normal cartilage, and although aggrecanase-generated SF-ARGS concentrations were increased 14-fold in OA and knee-injured patients compared with levels in knee-healthy reference subjects, the SF-FFGV concentrations did not notably change. The results of the present study suggest that MMPs are mainly involved in normal aggrecan turnover and might have a less-active role in aggrecan degradation during knee injury and OA.     

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid

Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.     

Serum CA19–9, cathepsin D,and matrix metalloproteinase‐7 as a diagnostic panel for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) accounts for 95% of pancreatic cancers. CA19‐9 is not widely used for screening PDAC due to its low sensitivity. Here, we studied the clinical usefulness of cathepsin D, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) for screening patients with PDAC. A total of 248 patients with PDAC and 216 control subjects were recruited (109 PDAC patients and 70 controls in the training set and 139 PDAC patients and 146 controls in the validation set). We measured serum levels of cathepsin D, TIMPs (?1, ?3, and ?4), and MMPs (?1, ?7, ?8, and ?9) using Fluorokine MAP multiplex kits. The concentrations of cathepsin D and MMP‐7 were significantly higher in PDAC subjects than control subjects. In the training set, the diagnostic sensitivity and AUC of the panel of CA19‐9, cathepsin D, and MMP‐7 for PDAC were increased to 88% and 0.900, compared to 74% and 0.835 of CA19‐9 single marker at 80% specificity. The sensitivity using cut‐off value of biomarker panel was significantly increased in the validation set as well as training set. Our findings indicate that a serum biomarker panel consisting of CA19‐9, cathepsin D, and MMP‐7 may provide the most effective screening test currently feasible for PDAC.     

Higher hepatic gene expression and serum levels of matrix metalloproteinase-2 are associated with steatohepatitis in non-alcoholic fatty liver diseases

We investigated the gene expression of tissue inhibitor metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) and serum levels of TIMPs, MMPs, and hyaluronic acid that are associated with liver fibrosis in 64 patients with nonalcoholic fatty liver diseases (NAFLD). Whereas, no differences were found between patients with and without nonalcoholic steatohepatitis (NASH) in serum levels of hyaluronic acid when excluding NASH patients with advanced fibrosis, the quantity of MMP2 mRNA in liver tissue and serum MMP2 levels were significantly higher in patients with NASH than those without, even focusing on patients with less advanced fibrosis, indicating the initiation of liver fibrosis.     

Gender dependent EMGs of runners resolved by time/frequency and principal pattern analysis.

A promising approach for the analysis of surface electromyograms is to use wavelets to determine the spectral distribution of the signal intensity at any time. The authors have recently proposed using non-linearly scaled wavelets to obtain intensity patterns, which reflect the spectral distribution at any given time point. Further analysis of intensity-patterns is greatly facilitated by representing them as linear combinations of a base set of principal-patterns. The weight with which each principal-pattern contributes to the intensity-pattern can be represented on a set of orthogonal axes that span a previously introduced pattern space. The purpose of the present study was to show how to use pattern space to discriminate and classify male and female runners based on the electromyograms of five muscles of the limb. The results showed that there were significant gender specific differences, which allowed more than a 95% correct classification of the subjects as males or females. Classification was possible irrespective of the shod condition while running. Gender specific differences occurred at well-defined time periods during the movement. Common to both genders was that spectral changes did not parallel the changes in total signal intensity.     

Analysis of the MMP-dependent and independent functions of tissue inhibitor of metalloproteinase-2 on the invasiveness of breast cancer cells

Matrix metalloproteinases (MMPs) are secreted endopeptidases that play an essential role in remodeling the extracellular matrix (ECM). MMPs are primarily active during development, when the majority of ECM remodeling events occurs. In adults, elevated MMP activity has been observed in many pathological conditions such as cancer and osteoarthritis. The proteolytic activity of MMPs is controlled by their natural inhibitors - the tissue inhibitor of metalloproteinases (TIMPs). In addition to blocking MMP-mediated proteolysis, TIMPs have a number of MMP-independent functions including binding to cell surface proteins thereby stimulating signaling cascades. TIMP-2, the most studied member of the family, can both inhibit and activate MMPs directly, as well as inhibit MMP activity indirectly by upregulating expression of RECK, a membrane anchored MMP regulator. While TIMP-2 has been shown to play important roles in breast cancer, we describe how the MMP-independent effects of TIMP-2 can modulate the invasiveness of MCF-7, T47D and MDA-MB-231 breast cancer cells. Using an ALA + TIMP-2 mutant which is devoid of MMP inhibition, but still capable of initiating specific cell signaling cascades, we show that TIMP-2 can differentially affect MMP activity and cellular invasiveness in both an MMP dependent and independent manner. More specifically, MMP activity and invasiveness is increased with the addition of exogenous TIMP-2 in poorly invasive cell lines whereas it is decreased in highly invasive cells lines (MDA-MB-231). Conversely, the addition of ALA + TIMP-2 resulted in decreased invasiveness regardless of cell line.     

Foot center of pressure manipulation and gait therapy influence lower limb muscle activation in patients with osteoarthritis of the knee

Background

Foot center of pressure (COP) manipulation has been associated with improved gait patterns. The purpose of this study was to determine lower limb muscle activation changes in knee osteoarthritis patients, both immediately after COP manipulation and when COP manipulation was combined with continuous gait therapy (AposTherapy).

Methods

Fourteen females with medial compartment knee osteoarthritis underwent EMG analyzes of key muscles of the leg. In the initial stage, trials were carried out at four COP positions. Following this, gait therapy was initiated for 3 months. The barefoot EMG was compared before and after therapy.

Results

The average EMG varied significantly with COP in at least one phase of stance in all examined muscles of the less symptomatic leg and in three muscles of the more symptomatic leg. After training, a significant increase in average EMG was observed in most muscles. Most muscles of the less symptomatic leg showed significantly increased peak EMG. Activity duration was shorter for all muscles of the less symptomatic leg (significant in the lateral gastrocnemius) and three muscles of the more symptomatic leg (significant in the biceps femoris). These results were associated with reduced pain, increased function and improved spatiotemporal parameters.

Conclusions

COP manipulation influences the muscle activation patterns of the leg in patients with knee osteoarthritis. When combined with a therapy program, muscle activity increases and activity duration decreases.     

MMPI Drug-Eluting IVC Filter Decreases Adhesion Between Caval Wall and Filter

The implantation of inferior vena cava (IVC) filter was a safe and effective therapy for preventing fatal pulmonary embolism. However, there are risks associated with long-term implantation of filters. Retrievable filters are designed to be removed, but may also remain permanently. Retrieval can reduce risk of long-term complications. The difficulty or impossibility of retrieval is still an issue of retrieval filter. The major causes of filters retrieval failure were intimal overgrowth and severely tilted filter with apex embedded into the caval wall. Matrix metalloproteinases (MMPs) play a key role in neointimal hyperplasia. It is documented that neointimal hyperplasia can be reduced by inhibiting MMP activity and hence smooth muscle cell migration. MMP inhibitors (MMPI) can potently inhibit the activity of MMPs. We hypothesize that a drug-eluting filter which contains MMPI may inhibit IVC neointimal hyperplasia and decrease the adhesion between vascular wall and filter struts. After implantation of drug-eluting retrieval filter, MMPI is released slowly at the sites where the filter struts are in contact with the caval wall; the activity of MMPs of caval wall will be inhibited, injury in basement membrane is decreased, migration of SMC maybe reduced, and the release of extracellular matrix maybe lessened. Finally, neointimal hyperplasia maybe inhibited, the adhesion between vascular wall and filter maybe weakened, the success rate maybe increased, and the vascular injury during retrieval maybe reduced. The hypothesis might improve the long-term prognosis of venous thromboembolism patients.     

Changes in EMG signals for the muscle tibialis anterior while running barefoot or with shoes resolved by non-linearly scaled wavelets

The purpose of this project was to study the EMG pattern of the tibialis anterior muscle in heel-toe running. Specifically, EMG changes in time, intensity and frequency shortly before and after heel-strike were addressed using an EMG-specific non-linearly scaled wavelets analysis. This method allowed extracting the time, intensity and frequency information inherent in the EMG signal at any time. The EMG signals of 40 male subjects were recorded for running barefoot and with shoes. The results confirmed that the pre-heel-strike EMG activities were typically seen at higher EMG frequencies (60-270Hz) while the post-heel-strike EMG activities resulted in lower frequency signals (10-90Hz). The timing of the pre-heel-strike EMG activities was not influenced by the used shoe conditions. The timing of the post-heel-strike EMG activities was significantly delayed when wearing shoes. The intensity of the pre-heel-strike muscle activity increased compared to the post-heel-strike one when wearing shoes. One can conclude that the activity of the tibialis anterior adjusts specifically to exterior conditions. The frequency shift between pre- and post heel-strike muscle activity were discussed with respect to activation of different motor units.     

The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue

Introduction  

Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients share many similarities with transformed cancer cells, including spontaneous production of matrix metalloproteinases (MMPs). Altered or chronic activation of proto-oncogenic Ras family GTPases is thought to contribute to inflammation and joint destruction in RA, and abrogation of Ras family signaling is therapeutic in animal models of RA. Recently, expression and post-translational modification of Ras guanine nucleotide releasing factor 1 (RasGRF1) was found to contribute to spontaneous MMP production in melanoma cancer cells. Here, we examine the potential relationship between RasGRF1 expression and MMP production in RA, reactive arthritis, and inflammatory osteoarthritis synovial tissue and FLS.