Effect of synthetic link N peptide on the expression of type I and type II collagens in human intervertebral disc cells

Intervertebral disc (IVD) degeneration is associated with proteolytic degradation of proteoglycan aggregates present within the extracellular matrix of the disc. Link N peptide (DHLSDNYTLDHDRAIH) is the N-terminal peptide of link protein, which stabilizes the proteoglycan aggregates. It is generated in vivo by proteolytic degradation during tissue turnover. It has been previously shown that this peptide can stimulate the synthesis of collagens by articular cartilage and bovine IVD cells in vitro. Being a synthetic peptide, Link N has considerable financial benefits for clinical use over recombinant growth factors because it is extremely cheap to produce. The purpose of the present study was to determine the effect of Link N on the expression of types I and II collagen and investigate the cellular mechanisms of Link N signal transduction in human IVD cells. The present results suggest that Link N stimulates the expression of types I and II collagen in human IVD cells. More specifically, Link N stimulated the expression of type I in nucleus pulposus (NP) cells, but not in annulus fibrosus cells. As Link N also decreased the phosphorylation of p38 in NP cells only, results suggest that p38 is a mediator of the effect of Link N on type I collagen expression. p38 is a member of the mitogen-activated protein kinase family highlighted by three major cascades: p38, c-Jun amino-terminal kinase, and extracellular signal-regulated kinase pathways. Link N showed no effect on the latter two pathways, suggesting a specific effect of Link N on the p38 cascade. On the other hand, Link N stimulated the expression of type II collagen in both NP and annulus fibrosus, suggesting that other mechanisms are implicated in the control of type II collagen expression in disc cells, without excluding p38 for the NP. In conclusion, the present study showed that Link N can modulate the expression of collagen in human IVD cells.     

Cyclic compression-induced p38 activation and subsequent MMP13 expression requires Rho/ROCK activity in bovine cartilage explants

Objective

Excessive mechanical stress on the cartilage causes the degradation of the matrix, leading to the osteoarthritis (OA). Matrix metalloproteinases 13 (MMP13) is a major catalytic enzyme in OA and p38 plays an important role in its induction. However, precise pathway inducing p38 activation has not been elucidated. We hypothesized here that the small GTPase Rho and its effector ROCK might function in upper part of the mechanical stress-induced matrix degeneration pathway.

Methods

Bovine metacarpal phalangeal articular cartilage explants were loaded with 1?MPa dynamic compression for 6?h with or without a ROCK specific inhibitor Y27632 or/and a p38 specific inhibitor SB202190. Then p38 phosphorylation and MMP13 expression were assessed by western blot or/and quantitative RT-PCR. Rho-activity was measured by pull-down assay using glutathione S-transferase fusion protein of Rho binding domain.

Results

Cyclic compression caused Rho activation, p38 phosphorylation and MMP13 expression. Both Y27632 and SB202190 were found to block the mechanical stress-enhanced p38 phosphorylation and subsequent MMP13 expression.

Conclusions

The present results show that p38 phosphorylation and MMP13 expression are regulated by Rho/ROCK activation, and support the potential novel pathway that Rho/ROCK is in the upper part of the mechanical stress-induced matrix degeneration cascade in cartilage comprised of p38 and MMP13.     

The Saccharomyces cerevisiae aldose reductase is implied in the metabolism of methylglyoxal in response to stress conditions

The enzyme aldose reductase plays an important role in the osmo-protection mechanism of diverse organisms. Here, we show that yeast aldose reductase is encoded by the GRE3 gene. Expression of GRE3 is carbon-source independent and up-regulated by different stress conditions, such as NaCl, H2O2, 39 degrees C and carbon starvation. Measurements of enzyme activity and intracellular sorbitol in wild-type cells also indicate that yeast aldose reductase is stress-regulated. Overexpression of GRE3 increases methylglyoxal tolerance in Saccharomyces cerevisiae. Furthermore, high expression of GRE3 complements the deficiency of the glyoxalase system of a glo1delta mutant strain. Consistent with this, in vitro and in vivo assays of yeast aldose reductase activity indicate that methylglyoxal is an endogenous substrate of aldose reductase. Furthermore, addition of NaCl or H2O2 to exponential-phase cells triggers an initial transient increase in the intracellular level of methylglyoxal, which is dependent on the Gre3p and Glo1p function. These observations indicate that the metabolism of methylglyoxal is stimulated under stress conditions; and they support a methylglyoxal degradative pathway, in which this compound is metabolised by the action of aldose reductase.     

31P and 3-fluoro-3-deoxy-D-glucose 19F in vivo NMR spectroscopy of aged rat brain

31P and 3-fluoro-3-deoxy-D-glucose (3-FDG) 19F nuclear magnetic resonance (NMR) spectroscopic investigations were performed on aged rat brain in vivo. Phosphodiester (PDE) was found to be significantly higher (p less than 0.05) in aged brain (18 months, n = 10) than adult controls (6 months, n = 10) suggesting accelerated phospholipid catabolism in aged brain. Inorganic phosphate (Pi) levels were significantly lower (p less than 0.05) in aged brain (n = 5) than in normal adult controls (n = 5). The sorbitol index, a measure of aldose reductase activities in vivo, determined by the 3-FDG 19F NMR method, revealed that aldose reductase activities were significantly higher (p less than 0.05) in aged brain.     

白藜芦醇对糖尿病肾病大鼠醛糖还原酶的影响

目的:观察白藜芦醇对糖尿病肾病大鼠醛糖还原酶的影响。方法:将48只雄性SD大鼠随机分为空白对照组、模型组、白藜芦醇低、中、高剂量组和依帕司他组(n=8)。除正常对照组外,其余各组大鼠腹腔注射STZ(55 mg.kg-1),成功造模后白藜芦醇组分别给予5、154、5 mg.kg-1白藜芦醇,依帕司他组给予10 mg.kg-1依帕司他,连续灌胃6 w后,检测大鼠血糖、体重,HE染色检测肾脏病理改变,ELISA法检测醛糖还原酶(AR)活性。结果:与正常对照组相比,糖尿病组血糖与AR活性明显升高(P<0.05),与模型组比较,白藜芦醇各组血糖与AR活性明显降低(P<0.05)。结论:白藜芦醇可降低糖尿病大鼠血糖,其降糖效应可能与抑制AR活性有关。     

Increased MMP-2 activity during intervertebral disc degeneration is correlated to MMP-14 levels

Intervertebral disc (IVD) degeneration is associated with the increased expression of several matrix metalloproteinases (MMPs), in particular MMP-2. However, little is known about the actual activity of MMP-2 in healthy and degenerated discs, or what mechanisms are involved in its activation. A major activation pathway involves complex formation with MMP-14 and a tissue inhibitor of metalloproteinases-2 (TIMP-2). In a series of 56 human IVDs, obtained at autopsy and graded according to the Thompson score (I-V), we analysed whether MMP-2 activity was increased in different stages of IVD degeneration and to what extent activation was related to the production of MMP-14 and TIMP-2. MMP-2 activation and production were quantified by gelatin zymography. Immunohistochemical staining of MMP-14 and TIMP-2 was quantified with a video overlay-based system. A positive correlation was observed between the amount of active MMP-2 and pro-MMP-2 and degeneration grade (p < 0.001, correlation coefficient (CC) 0.557; and p < 0.001, CC 0.556, respectively). MMP-2 activity correlated positively with MMP-14 and less strongly with TIMP-2 (p = 0.001, CC 0.436; and p = 0.03, CC 0.288, respectively). Moreover, immunopositivity for MMP-14 correlated to degeneration grade (p = 0.002, CC 0.398). IVD degeneration was associated with the activity of MMP-2 and the correlation of its activation with MMP-14 production suggests MMP-14 activates MMP-2 during degeneration. As MMP-14 is capable of activating several other enzymes that are also thought to be involved in IVD degeneration, it may be a key mediator of the degenerative process.     

Tension Force Downregulates Matrix Metalloproteinase Expression and Upregulates the Expression of Their Inhibitors through MAPK Signaling Pathways in MC3T3-E1 cells

Objective: Matrix metalloproteinases (MMPs), produced by osteoblasts, catalyze the turnover of extracellular matrix (ECM) molecules in osteoid, and the regulation of MMP activity depends on interactions between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We focused on the degradation process of ECM in osteoid that was exposed to mechanical strain, and conducted an in vitro study using MC3T3-E1 osteoblastic cells to examine the effects of tension force (TF) on the expression of MMPs and TIMPs, and activation of mitogen-activated protein kinase (MAPK) pathways.Design: Cells were incubated on flexible-bottomed culture plates and stimulated with or without cyclic TF for 24 hours. The expression of MMPs and TIMPs was examined at mRNA and protein levels by real-time RT-PCR and Western blotting, respectively. The phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, and stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) were examined by Western blotting.Results: TF decreased the expression of MMP-1, -3, -13 and phosphorylated ERK1/2. In contrast, TF increased the expression of TIMP-2, -3 and phosphorylated SAPK/JNK. The expression of MMP-2, -14, TIMP-1, -4 and phosphorylated p38 MAPK was unaffected by TF. MMP-1, -3 and -13 expression decreased in cells treated with the ERK inhibitor PD98059 compared with untreated control cells. The JNK inhibitor SP600125 inhibited the TF-induced upregulation of TIMP-2 and -3.Conclusions: The results suggest that TF suppresses the degradation process that occurs during ECM turnover in osteoid via decreased production of MMP-1, -3 and -13, and increased production of TIMP-2 and -3 through the MAPK signaling pathways in osteoblasts.     

Current Knowledge and Future Therapeutic Prospects in Symptomatic Intervertebral Disc Degeneration

Intervertebral disc (IVD) degeneration is the main source of intractable lower back pain, and symptomatic IVD degeneration could be due to different degeneration mechanisms. In this article, we describe the molecular basis of symptomatic IVD degenerative disc diseases (DDDs), emphasizing the role of degeneration, inflammation, angiogenesis, and extracellular matrix (ECM) regulation during this process. In symptomatic DDD, pro-inflammatory mediators modulate catabolic reactions, resulting in changes in ECM homeostasis and, finally, neural/vascular ingrowth-related chronic intractable discogenic pain. In ECM homeostasis, anabolic protein-regulating genes show reduced expression and changes in ECM production, while matrix metalloproteinase gene expression increases and results in aggressive ECM degradation. The resultant loss of normal IVD viscoelasticity and a concomitant change in ECM composition are key mechanisms in DDDs. During inflammation, a macrophage-related cascade is represented by the secretion of high levels of pro-inflammatory cytokines, which induce inflammation. Aberrant angiogenesis is considered a key initiative pathologic step in symptomatic DDD. In reflection of angiogenesis, vascular endothelial growth factor expression is regulated by hypoxia-inducible factor-1 in the hypoxic conditions of IVDs. Furthermore, IVD cells undergoing degeneration potentially enhance neovascularization by secreting large amounts of angiogenic cytokines, which penetrate the IVD from the outer annulus fibrosus, extending deep into the outer part of the nucleus pulposus. Based on current knowledge, a multi-disciplinary approach is needed in all aspects of spinal research, starting from basic research to clinical applications, as this will provide information regarding treatments for DDDs and discogenic pain.     

Hepatocyte production of modulators of extracellular liver matrix in normal and cirrhotic rat liver

In the present study, we found collagenolytic and gelatinolytic activity in the supernatants of hepatocyte cultures from rats with experimental CCl(4)-induced liver cirrhosis, in levels significantly higher than in comparable supernatants of hepatocyte cultures from normal rats. In addition, we clearly detected the messenger ribonucleic acids (mRNA) of four matrix metalloproteinases (MMP-2, MMP-3, MMP-10, and MMP-13) and of two tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2) in hepatocytes from both normal and cirrhotic rats by RT-PCR and by in situ hybridization. Finally, we demonstrated MMP-2, MMP-3, and MMP-13 and TIMP-1 and TIMP-2 proteins in the same hepatocyte preparations by immunostaining. We conclude that rat hepatocytes produce the major enzymes and inhibitors involved in liver ECM modulation and therefore suggests that they might participate actively in the pathophysiology of liver cirrhosis in rats.     

Expression of receptors for putative anabolic growth factors in human intervertebral disc: implications for repair and regeneration of the disc

Low back pain (LBP) is a common, debilitating and economically important disorder. Current evidence implicates loss of intervertebral disc (IVD) matrix consequent upon 'degeneration' as a major cause of LBP. Degeneration of the IVD involves increases in degradative enzymes and decreases in the extracellular matrix (ECM) component in a process that is controlled by a range of cytokines and growth factors. Studies have suggested using anabolic growth factors to regenerate the normal matrix of the IVD, hence restoring disc height and reversing degenerative disc disease. However, for such therapies to be successful it is vital that the target cells (i.e. the disc cells) express the appropriate receptors. This immunohistochemical study has for the first time investigated the expression and localization of four potentially beneficial growth factor receptors (i.e. TGFbetaRII, BMPRII, FGFR3 and IGFRI) in non-degenerate and degenerate human IVDs. Receptor expression was quantified across regions of the normal and degenerate disc and showed that cells of the nucleus pulposus (NP) and inner annulus fibrosus (IAF) expressed significantly higher levels of the four growth factor receptors investigated. There were no significant differences between the four growth factor expression in non-degenerate and degenerate biopsies. However, expression of TGFbetaRII, FGFR3 and IGFRI, but not BMP RII, were observed in the ingrowing blood vessels that characterize part of the disease aetiology. In conclusion, this study has demonstrated the expression of the four growth factor receptors at similar levels in the chondrocyte-like cells of the NP and IAF in both non-degenerate and degenerate discs, implicating a role in normal disc homeostasis and suggesting that the application of these growth factors to the degenerate human IVD would stimulate matrix production. However, the expression of some of the growth factor receptors on ingrowing blood vessels might be problematic in a therapeutic approach.     

抗氧化剂对系膜细胞醛糖还原酶活性的影响

目的：观察抗氧化剂对高糖培养下肾小球系膜细胞(MC)内醛糖还原酶(AR)活性的影响，探讨抗氧化剂治疗糖尿病并发症的分子机制。方法:将牛肾小球系膜细胞培养于含高糖的培养基中3周，同时加入抗氧化剂过氧化物酶和DMSO，采用间接法观察抗氧化剂对细胞内醛糖还原酶活性的影响结果:高糖作用下系膜细胞内山梨醇含量增加，表明醛糖还原酶活性增高，而抗氧化剂能抑制醛糖还原酶活性的增高。结论:氧化应激和多元醇通路关系密切，抗氧化剂通过降低AR的活性和清除多元醇通路中产生的氧自由基而对糖尿病并发症有治疗作用，为临床运用尤其是早期运用抗氧化剂治疗糖尿病提供了理论依据。     

Administration of an aldose reductase inhibitor, ONO-2235, to streptozotocin-diabetic mice restores reductions of DRG neuronal attachment to extracellular matrix proteins in vitro

Attachments of cultured dorsal root ganglion (DRG) neurons to the extracellular matrix (ECM) proteins (type I and IV collagens, laminin and fibronectin) and the adhesion ligand arginine-glycine-aspartic acid (RGD) were impaired in mice 2 weeks after the induction of diabetes by streptozotocin (STZ). However, administration of the aldose reductase inhibitor, ONO-2235, to the STZ-diabetic mice for 1 week restored DRG neuronal attachment to the ECM proteins and RGD to a level close to normal mice. These results suggest that activation of the aldose reductase and subsequent metabolic disorders in diabetic animals may play an important role in detrimental alterations of the neuronal cell-surface receptors for the ECM proteins.     

Intervertebral disc ageing and degeneration: The antiapoptotic effect of oestrogen

As an important part of the spinal column, the intervertebral disc (IVD) plays an important role in the intervertebral juncture and spinal movement in general. IVD degeneration (IVDD), which mimics disc ageing but at an accelerated rate, is a common and chronic process that results in severe spinal symptoms, such as lower back pain. It is generally assumed that lower back pain caused by IVDD can also develop secondary conditions, including spinal canal stenosis, spinal segmental instability, osteophyte formation, disc herniation and spinal cord and nerve root compression. Over the past few years, many researchers around the world have widely studied the relevance between oestrogen and IVDD, indicating that oestrogen can effectively alleviate IVDD development by inhibiting the apoptosis of IVD cells. Oestrogen can decrease IVD cell apoptosis in multiple ways, including the inhibition of the inflammatory cytokines IL-1β and TNF-α, reducing catabolism because of inhibition of matrix metalloproteinases, upregulating integrin α₂β₁ and IVD anabolism, activating the PI3K/Akt pathway, decreasing oxidative damage and promoting autophagy. In this article, we perform an overview of the literature regarding the antiapoptotic effect of oestrogen in IVDD.     

In vivo pharmacokinetics of aldose reductase inhibitors: 3-fluoro-3-deoxy-D-glucose NMR studies in rat brains

Direct quantification of the inhibitory effects of orally administered drugs (sorbinil, cyclandelate and sulindac) on aldose reductase activities in rat brains was performed non-invasively using the 3-fluoro-3-deoxy-D-glucose (3-FDG) 19F NMR spectroscopic technique. Quantitative data obtained directly from the target organ (brain) allowed for unprecedentedly accurate analysis of drug effects in the brain in vivo. Sorbinil, a potent aldose reductase inhibitor, exhibited a classic monophasic organ response, whereas cyclandelate and sulindac showed biphasic suppression patterns. The latter indicate that there are metabolites of these drugs which possess aldose reductase inhibitory activities. The estimated potency of aldose reductase inhibition for each of the three drugs in this study was significantly discrepant from the in vitro studies indicating the complicated nature of the bioavailability of a pharmaceutical agent in vivo, especially where pharmacologically active metabolites of a given drug are involved. Our method allows for a direct quantitative assay and hence the most reliable technique for evaluating aldose reductase inhibitory activities in the target organ.     

连翘苷元通过抑制TLR4介导的NF-κB信号通路减轻大鼠骨关节炎软组织损伤和基质降解

目的研究连翘苷元调控TLR4介导的NF-κB信号通路的活化对骨关节炎大鼠软组织损伤和基质降解的影响。方法建立骨关节炎大鼠模型,将大鼠随机分为6组:健康对照组,模型组,连翘苷元低、中、高剂量组和双醋瑞因组进行后续实验;苏木素-伊红染色和番红O-固绿染色检测大鼠骨关节病理损伤程度;ELISA检测炎症因子的含量;蛋白免疫印迹检测半胱氨酸蛋白酶-3、半胱氨酸蛋白酶-9、聚集蛋白聚糖、基质金属蛋白酶13、Ⅱ型胶原蛋白、Toll样受体4、髓样分化因子88、核因子κB蛋白表达水平。结果与模型组相比较,连翘苷元中、高剂量组和双醋瑞因组骨关节病理损伤程度明显改善,Caspase-3、Caspase-9蛋白水平显著降低(P<0.05),Bcl-2/Bax比值显著升高(P<0.05),Aggrecan、type II collagen(ColⅡ)蛋白水平显著升高(P<0.05),MMP-13蛋白水平显著降低(P<0.05),IL-6、IL-17、TNF-α、MCP-1含量显著降低(P<0.05),TLR-4、MyD88、NF-κB p65蛋白水平显著降低(P<0.05)。结论连翘苷元抑制TLR4介导的NF-κB信号通路的活化对骨关节炎大鼠软组织损伤和基质降解具有修复作用。     

New insights into the roles of matrix metalloproteinases in colorectal cancer development and progression

This review outlines new concepts that are emerging for the functions of matrix metalloproteinases in colorectal cancer development and progression. The two main concepts that will be discussed are the role of matrix metalloproteinases in the early stages of colorectal tumour development and the functional mechanisms by which matrix metalloproteinases contribute to colorectal tumour invasion and metastasis. The matrix metalloproteinases are a group of enzymes, which have been best characterized for their ability to degrade extracellular matrix proteins and thus they have been extensively studied in tumour invasion. It is now becoming recognized that the matrix metalloproteinases have key roles in a variety of biological processes that are distinct from their well-defined role in matrix degradation. This group of enzymes has been shown to interact with a broad range of non-matrix proteins including growth factors and their receptors, mediators of apoptosis, and cell adhesion molecules. The elucidation of novel biological roles for the matrix metalloproteinases also challenges the current predominant concept of matrix metalloproteinases as enzymes only involved in matrix degradation. Recent studies have shown that several matrix metalloproteinases, especially matrilysin (MMP-7), interact with the specific molecular genetic and signalling pathways involved in colorectal cancer development. In particular, matrilysin is activated at an early stage of colorectal tumourigenesis by the beta-catenin signalling pathway. Furthermore, studies are now elucidating specific mechanisms by which individual matrix metalloproteinases, especially membrane-type matrix metalloproteinases, interact with specific cell adhesion molecules and cytoskeletal proteins and thus contribute dynamically to colorectal tumour invasion.     

Diversity of intervertebral disc cells: phenotype and function

The intervertebral disc (IVD) is a moderately moving joint that is located between the bony vertebrae and provides flexibility and load transmission throughout the spinal column. The disc is composed of different but interrelated tissues, including the central highly hydrated nucleus pulposus (NP), the surrounding elastic and fibrous annulus fibrosus (AF), and the cartilaginous endplate (CEP), which provides the connection to the vertebral bodies. Each of these tissues has a different function and consists of a specific matrix structure that is maintained by a cell population with distinct phenotype. Although the healthy IVD is able to balance the slow matrix turnover of synthesis and degradation, this balance is often disturbed, leading to degenerative disorders. Successful therapeutic management of IVD degeneration requires a profound understanding of the cellular and molecular characteristics of the functional IVD. Hence, the phenotype of IVD cells has been of significant interest from multiple perspectives, including development, growth, remodelling, degeneration and repair. One major challenge that complicates our understanding of the disc cells is that both the cellular phenotype and the extracellular matrix strongly depend on disc maturity and health and as a consequence are continuously evolving. This review delineates the diversity of the cell types found in the intervertebral disc, with emphasis on human, but with reference to other species. The cells of the NP appear rounded and express a proteoglycan-rich matrix, whereas the more elongated AF cells are embedded in a collagen fibre matrix and the CEPs represent a layer of cartilage. Even though all disc cells have often been referred to as ‘intervertebral disc chondrocytes’, distinct phenotypical differences in comparison with articular chondrocytes exist and have been reported recently. The availability of more specific markers has also improved our understanding of progenitor cell differentiation towards an IVD cell phenotype. Ultimately, new cell- and tissue-engineering approaches to regenerative therapies will only be successful if the specific characteristics of the individual tissues and their context in the function of the whole organ, are taken into consideration.     

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

This study was aimed at evaluating the potent and specific aldose reductase inhibitor fidarestat, on diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis. Control and streptozotocin-diabetic rats were treated with or without fidarestat (16 mg kg(-1)d(-1)) for 10 weeks after an initial 2-week period without treatment. Lens changes were evaluated by indirect ophthalmoscopy and portable slit lamp. Nitrotyrosine, poly(ADP-ribose), and glial fibrillary acidic protein expression were assessed by immunohistochemistry. The rate of apoptosis was quantified in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. To dissect the effects of high glucose exposure in retinal microvascular cells, primary bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without fidarestat (10 microM) for 3-14 days. Apoptosis was assessed by TUNEL assay, nitrotyrosine and poly(ADP-ribose) by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Fidarestat treatment prevented diabetic cataract formation and counteracted retinal nitrosative stress, and poly(ADP-ribose) polymerase activation, as well as glial activation. The number of TUNEL-positive nuclei (mean +/- SEM) was increased approximately 4-fold in diabetic rats vs. controls (207+/-33 vs. 49+/-4, p<0.01), and this increase was partially prevented by fidarestat (106+/-34, p<0.05 vs. untreated diabetic group). The apoptotic cell number increased with the prolongation of exposure of both pericytes and endothelial cells to high glucose levels. Fidarestat counteracted nitrotyrosine and poly(ADP-ribose) accumulation and apoptosis in both cell types. Antiapoptotic effect of fidarestat in high glucose-exposed retinal pericytes was not associated with the inhibition of Bax or increase in Bcl-2 expression. In conclusion, the findings, i) support an important role for aldose reductase in diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis, and ii) provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for the prevention and treatment of diabetic ocular complications.     

Lipodermatosclerosis and the significance of proteolytic remodeling in the pathogenesis of venous ulceration (Review)

The preceding stage of venous ulceration represents a scleroderma-like hardening of the skin called lipodermatosclerosis. Clinical stages such as lipodermatosclerosis and venous ulceration, which succeed one another are highly associated to chronic venous insufficiency. Lipodermatosclerosis is characterized by fibrous scar tissue of the reticular dermis built up of collagen bundles and loss of cellular components, whereas venous ulceration is characterized by total loss of epidermis and partially of matrix structures in the upper dermis. There is a growing recognition that an excessive proteolytic activity by proteases, in particular that of matrix metalloproteinases and fibrinolytic factors of the plasminogen activation system may be a key feature in the pathophysiological understanding of venous leg ulcer formation. Lipodermatosclerosis displays an intense ongoing proteolytic process by elevated matrix metalloproteinase activity, as recently shown on different molecular and biological levels. Elevated expression on mRNA and protein level of matrix metalloproteinases and fibrinolytic factors of the plasminogen activation system have been detected in liposclerotic skin lesions. In addition, matrix metalloproteinases were proteolytically activated confirmed by zymography experiments and collagen degradation assays. Therefore it is well conceivable, that proteolytic enzymes of matrix metalloproteinases could initiate an elevated turnover of the extracellular matrix with subsequent breakdown of the matrix scaffold finally resulting in venous ulceration.