Deletion of Col15a1 Modulates the Tumour Extracellular Matrix and Leads to Increased Tumour Growth in the MMTV-PyMT Mouse Mammary Carcinoma Model.

Basement membrane (BM) zone-associated collagen XV (ColXV) has been shown to suppress the malignancy of tumour cells, and its restin domain can inhibit angiogenesis. In human breast cancer, as well as in many other human carcinomas, ColXV is lost from the epithelial BM zone prior to tumour invasion. Here, we addressed the roles of ColXV in breast carcinogenesis using the transgenic MMTV-PyMT mouse mammary carcinoma model. We show here for the first time that the inactivation of Col15a1 in mice leads to changes in the fibrillar tumour matrix and to increased mammary tumour growth. ColXV is expressed by myoepithelial and endothelial cells in mammary tumours and is lost from the ductal BM along with the loss of the myoepithelial layer during cancer progression while persisting in blood vessels and capillaries, even in invasive tumours. However, despite the absence of anti-angiogenic restin domain, neovascularisation was reduced rather than increased in the ColXV-deficient mammary tumours compared to controls. We also show that, in robust tumour cell transplantation models or in a chemical-induced fibrosarcoma model, the inactivation of Col15a1 does not affect tumour growth or angiogenesis. In conclusion, our results support the proposed tumour suppressor function of ColXV in mammary carcinogenesis and reveal diverse roles of this collagen in different cancer types.

Familial Short Stature-A Novel Phenotype of Growth Plate Collagenopathies.

CONTEXT: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. OBJECTIVE: This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. METHODS: Eighty-seven FSS children (pretreatment height ≤ -2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. RESULTS: A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of -3.1 SD to -2.6 SD and to -2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by -0.67 to +1.0 SD and -0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent's height, respectively. CONCLUSION: Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.

Knockdown of CTRP6 inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells through regulating the Akt/NF-κB pathway.

C1qTNF-related protein 6 (CTRP6) is a member of the CTRP family and exerts a key role in the progression of diabetes mellitus. However, the role of CTRP6 in diabetic nephropathy remains unknown. The present study was designed to examine the roles of CTRP6 in diabetic nephropathy and explore the potential molecular mechanisms. Our results showed that the expression level of CTRP6 was significantly increased in high glucose (HG)-stimulated glomerular mesangial cells (MCs). The following loss/gain-of-function assays demonstrated that CTRP6 knockdown significantly inhibited HG-induced reactive oxygen species (ROS) production in MCs. CTRP6 knockdown caused significant decreases in tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6 production levels in HG-induced MCs. Moreover, knockdown of CTRP6 inhibited HG-stimulated extracellular matrix (ECM) accumulation in MCs characterized by decreased expression and production levels of fibronectin (FN) and collagen IV (Col IV). Furthermore, CTRP6 knockdown suppressed HG-induced the activation of Akt/NF-κB pathway in MCs, while overexpression of CTRP6 exhibited the opposite effects. Treatment with LY294002, an inhibitor of Akt, reversed the induction effects of CTRP6 overexpression on ROS production, inflammation and ECM accumulation in MCs. In conclusion, these findings demonstrated that CTRP6 knockdown inhibits HG-induced ROS production, inflammation and ECM accumulation in MCs, which were mediated by the inactivation of the Akt/NF-κB pathway. The roles of CTRP6 in diabetic nephropathy provided evidence for its therapeutic potential for the treatment of diabetic nephropathy.

Ultrasonido intraquirúrgico como medio de estimulación del colágeno aplicado a la blefaroplastia del párpado inferior / Intrasurgical ultrasound as a means collagen stimulation applied to lower eyelid blepharoplasty

El colágeno1 es una proteína que desempeña un papel crítico en la arquitectura de la piel. La cualidad que transmite es la fuerza y resistencia. La esencia de este trabajo es demostrar que con la estimulación del colágeno de la piel del párpado inferior se logra restablecer la piel necesaria para que tenga un aspecto agradable, sin necesidad de recurrir a la exéresis. Al conseguir el calentamiento del colágeno, la piel recobra propiedades como elasticidad, retracción y retención, cualidades propias de una piel joven. La idea que se quiere transmitir es que se puede mejorar la piel sin correr el riesgo6,7 de una asimetría o una desmesura que termine con ectropión o retracciones cicatrizales luego de extracción de piel. Este es un procedimiento rápido que no entorpece el normal desempeño quirúrgico, extremadamente seguro ya que se recurre a una estimulación proteica sin sacar piel y perdura el resultado en el tiempo o sea que es efi caz

Collagen1 is a protein plays a critical role in skin architecture. The quality that comes through is the strength and endurance. The essence of this paper is to demonstrate that collagen stimulation of the lower eyelid skin, manages to restore the skin necessary to have a nice look without resorting to excerecis. By getting the heating of collagen and recovers elasticity properties, shrinkage and retention qualities of youthful skin. The idea to be conveyed, is that you can improve the skin without running the risk6,7 of an asymmetry or disproportion to end scarring ectropion or retraction after removal of skin. This is a quick procedure that does not hinder the normal surgical performance, extremely safe because it uses a non-protein stimulation by removing skin and the result lasts over time or whether it is eff ective.

Can transcutaneous electrical nerve stimulation improve achilles tendon healing in rats?

BACKGROUND: Tendon injury is one of the most frequent injuries in sports activities. TENS is a physical agent used in the treatment of pain but its influence on the tendon's healing process is unclear. OBJECTIVE: To evaluate the influence of TENS on the healing of partial rupture of the Achilles tendon in rats. METHOD: Sixty Wistar rats were submitted to a partial rupture of the Achilles tendon by direct trauma and randomized into six groups (TENS or Sham stimulation) and the time of evaluation (7, 14, and 21 days post-injury). Burst TENS was applied for 30 minutes, 6 days, 100 Hz frequency, 2 Hz burst frequency, 200 µs pulse duration, and 300 ms pulse train duration. Microscopic analyses were performed to quantify the blood vessels and mast cells, birefringence to quantify collagen fiber alignment, and immunohistochemistry to quantify types I and III collagen fibers. RESULTS: A significant interaction was observed for collagen type I (p=0.020) where the TENS group presented lower percentage in 14 days after the lesion (p=0.33). The main group effect showed that the TENS group presented worse collagen fiber alignment (p=0.001) and lower percentage of collagen III (p=0.001) and the main time effect (p=0.001) showed decreased percentage of collagen III at 7 days (p=0.001) and 14 days (p=0.001) after lesion when compared to 21 days. CONCLUSIONS: Burst TENS inhibited collagen I and III production and impaired its alignment during healing of partial rupture of the Achilles tendon in rats.

Basement membrane zone collagens XV and XVIII/proteoglycans mediate leukocyte influx in renal ischemia/reperfusion.

Collagen type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these collagens are associated with eye, muscle and microvessel phenotypes. We now describe a novel role for these collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in collagen XV or collagen XVIII, and their compound mutant, as well as the wild-type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the collagen XV, collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-type mice (all p<0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-α in double mutant mice compared to wildtype mice. Both type XV and type XVIII collagen bear glycosaminoglycan side chains and an in vitro approach with recombinant collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone collagen/proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal ischemia/reperfusion and might be potential intervention targets for the reduction of inflammation in this condition.

[DEFINITION OF INTERRELATION BETWEEN AMINOACID COMPOSITION OF URINE AND BONE TISSUE DENSITY AT CHILDREN WITH ACUTE LEUKAEMIA FOR ONCOHEMATOLOGICAL PATHOLOGY RISK GROUP FORMATION].

Age and sexual indexies of densitometry at patients with acute leukemia (AL) and healthy children are presented. 31% of children with AL during the initial period of disease had manifestations of the osteopenic syndrome. At patients with AL more often than at healthy children anomalies of development of front part of skull are defined. The partial contribution of free and peptides-connencted oxyproline in urine at AL patients differs in comparison with control group that is caused by modification or deficiency of the corresponding enzymes. 30% of patients with AL had raised concentration of free oxyproline in urine, and lowered glycine concentration that testifies to the increased disintegration of collagen and deficiency of tile plastic material necessary for collagene-forming processes. The obtained data should be considered for forming of risk group on oncohematological pathology at children.

Specific binding of collagen Q to the neuromuscular junction is exploited to cure congenital myasthenia and to explore bases of myasthenia gravis.

Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ) in the form of asymmetric AChE (AChE/ColQ). The C-terminal domain of ColQ binds to MuSK, the muscle-specific receptor tyrosine kinase, that mediates a signal for acetylcholine receptor (AChR) clustering at the NMJ. ColQ also binds to heparan sulfate proteoglycans including perlecan. Congenital defects of ColQ cause endplate AChE deficiency. A single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq-/- mice rescued motor functions, synaptic transmission, and the ultrastructure of NMJ. We also injected AAV1-COLQ-IRES-EGFP to the left tibialis anterior and observed colocalization of AChE/ColQ at all the examined NMJs of the non-injected limbs. Additionally, injection of purified recombinant AChE/ColQ protein complex into gluteus maximus accumulated AChE in non-injected forelimbs. These observations suggest that the tissue-targeting signal of ColQ can be exploited to specifically deliver the transgene product to the target tissue. MuSK antibody-positive myasthenia gravis (MG) accounts for 5-15% of autoimmune MG. As AChR deficiency is typically mild and as cholinesterase inhibitors are generally ineffective or worsen myasthenic symptoms, we asked if the patient's MuSK-IgG interferes with binding of ColQ to MuSK. In vitro overlay of AChE/ColQ to muscle sections of Colq-/- mice revealed that MuSK-IgG blocks binding of ColQ to the NMJ. In vitro plate-binding of MuSK to ColQ disclosed that MuSK-IgG exerts a dose-dependent block of MuSK-ColQ interaction. In addition, passive transfer of MuSK-IgG to mice reduced the size and density of ColQ to ∼10% of controls and had a lesser effect on the sizes and densities of AChR and MuSK. Elucidation of molecular mechanisms of specific binding of ColQ to the NMJ enabled us to ameliorate devastating myasthenic symptoms of Colq-/- mice and to reveal bases of anti-MuSK MG.

Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities.

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder. All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose. Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints. Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay. Mutation analysis revealed the presence of disease-causing variants in PYCR1, including a novel deletion of the entire PYCR1 gene in one family, and in each of the other patients the homozygous missense mutations c.616G > A (p.Gly206Arg), c.89T > A (p.Ile30Lys) and c.572G > A (p.Gly191Glu) respectively, the latter two of which are novel. Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size. In conclusion, this study adds information on the natural course of PYCR1 deficiency and sheds light on the pathophysiology of this disorder. However, the exact pathogenesis of this new disorder and the role of proline in the development of the clinical phenotype remain to be fully explained.

Animal models of acute photodamage: comparisons of anatomic, cellular and molecular responses in C57BL/6J, SKH1 and Balb/c mice.

Human cutaneous photodamage is a major medical problem that includes premature aging and fragility of the skin. Nonxenografted animal models have not been comparatively evaluated for how well they resemble the changes seen in human skin. Here, we sought to identify a suitable mouse model that recapitulates key anatomic, cellular and molecular responses observed in human skin during acute UV exposure. Adult females from three strains of mice, C57BL/6J, SKH1 and Balb/c were exposed to UVB and then evaluated 3 or 20 h after the last irradiation. Skin from UVB-exposed C57BL/6J mice showed features resembling human photodamage, including epidermal thickening, infiltration of the dermis with inflammatory cells, induction of tumor necrosis factor-α (TNF-α) mRNA, accumulation of glycosaminoglycans, particularly hyaluronan in the epidermis and loss of collagen. Hairless SKH1 mouse skin responded similarly, but without any induction of TNF-α mRNA or chondroitin sulfate. Irradiated Balb/c mice were the least similar to humans. Our results in C57BL/6J mice and to a lesser extent in SKH1 mice, show cutaneous responses to a course of UVB-irradiation that mirror those seen in human skin. Proper choice of model is critical for investigating cellular and molecular mechanisms of photodamage and photoaging.

Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease.

Type IV collagen is a predominant component of basement membranes, and glomeruli of a kidney filter approximately 70-90 liters of plasma every day through a specialized glomerular basement membrane (GBM). In Alport syndrome, a progressive disease primarily affecting kidneys, mutations in GBM-associated type IV collagen genes (COL4A3, COL4A4, or COL4A5) lead to basement membrane structural defects, proteinuria, renal failure, and an absence of all three GBM collagen triple helical chains because of obligatory posttranslational assembly requirements. Here, we demonstrate that transplantation of wild-type bone marrow (BM) into irradiated COL4A3(-/-) mice results in a possible recruitment of BM-derived progenitor cells as epithelial cells (podocytes) and mesangial cells within the damaged glomerulus, leading to a partial restoration of expression of the type IV collagen alpha3 chain with concomitant emergence of alpha4 and alpha5 chain expression, improved glomerular architecture associated with a significant reduction in proteinuria, and improvement in overall kidney histology compared with untreated COL4A3(-/-) mice or irradiated COL4A3(-/-) mice with BM from adult COL4A3(-/-) mice. The alpha3(IV) collagen produced by BM-derived podocytes integrates into the GBM and associates with other alpha-chains to form type IV collagen triple helical networks. This study demonstrates that BM-derived stem cells can offer a viable strategy for repairing basement membrane defects and conferring therapeutic benefit for patients with Alport syndrome.

Lack of telopeptides in fibrillar collagen I promotes the invasion of a metastatic breast tumor cell line.

Defective fibrillar collagen polymerization in primary tumors has been correlated with increased metastasis. However, it is unclear how collagen organization influences tumor invasion. In this study, we show that collagen I polymerized without telopeptides (the flanking regions of collagen molecules) can differentially affect the three-dimensional migration of mammary carcinoma cells. MDA-MB-231 cells capable of proteolytic degradation and mesenchymal motion, invaded telopeptide-intact and telopeptide-free collagen gels to the same extent. In contrast, MDA-MB-435S cells, with typical features of amoeboid cells (poor collagenolytic activity, rounded cell morphology), were 5-fold more invasive in telopeptide-free than telopeptide-intact collagen. A fraction of the MDA-MB-435S cells that invaded telopeptide-intact or telopeptide-free collagen had a rounded morphology; however, in telopeptide-free collagen, a significant fraction of the cells switched from a rounded to elongated morphology (protrusion formation). The dynamic changes in cellular shape facilitated MDA-MB-435S locomotion through the narrow interfiber gaps, which were smaller than cell diameters. Based on the spherical morphology of MDA-MB-435S cells, we tested if the changes in cell shape and invasion were related to RhoA-ROCK activity; GTP-bound RhoA was measured in pull-down assays. RhoA activity was 1.8-fold higher for MDA-MB-435S cells seeded on telopeptide-free than telopeptide-intact collagen. Y27632 inhibition of ROCK, a Rho effector, significantly reduced the changes in cellular morphodynamics and the invasion of MDA-MB-435S cells but did not alter the invasion of MDA-MB-231 cells. Thus, the higher RhoA activity of MDA-MB-435S cells in telopeptide-free collagen enhances the changes in cellular morphodynamics associated with motility and invasion.

Envelhecimento e descenso genital: o papel do colágeno / Aging and genital prolapse: the role of collagen

O Aumento da expectativa de vida deu-se em ambos os sexos, em todas as idades, sendo que os mais expressivos incrementos foram observados na população feminina. Caso se queira adicionar qualidade de vida à longevidade dessas mulheres, deve-se estar atento também a doenças como o descenso genital, que, certamente, não diminui a longevidade, mas reduz drasticamente a qualidade de vida, limitando o convívio social e o desempenho das atividades diárias. Em função disso, os autores desenvolvem uma revisão relativa à gênese do descenso genital, abordando aspectos pertinentes ao envelhecimento do trato genitourinário, fatores de risco, anatomia e biomecânica da doença, incluindo, o papel desempenhado pelo colágeno, além das implicações clínicas relacionadas a todos esses aspectos

[Genital prolapse in women and articular hypermobility syndrome in connective tissue dysplasia]. / Vzaimosviaz' vypadeniia polovykh organov u zhenshchin s sindromom gipermobil'nosti sustavov pri displazii soedinitel'noi tkani.

AIM: To examine relationships between genital prolapse and joint hypermobility (JHM), between GP severity and degree of JHM, to reveal causes of GP in JHM patients. MATERIAL AND METHODS: A total of 208 females with GP (mean age 38.9 years) entered the trial. They were divided into three groups by severity of connective tissue dysplasia (CTD): with mild CTD--16.3%, moderate CTD--35.6% and severe CTD--48.1%. The following methods of investigation were used: podometric Freedland's technique, ultrasonic investigation of the gall bladder, kidneys, echocardiography, morphological study of platelets, morphological and immunohistochemical study of the ligaments. RESULTS: In GP patients JHM occurred in 41.8% patients. Hypermobility of large joints reaches 38.9%, large--20.7%. Such associated manifestations of CTD as flatfoot, JHM, deformation of the spine, varicosity, predisposition to vegetovascular dysfunctions, mitral prolapse, arrhythmia, impaired conduction, refraction, gastroptosis, nephroptosis, hernias were observed in 69.2, 46.1, 38, 53.8, 49, 43.3, 38, 19.2, 12, 6.7, 14.4%, respectively. The morphological changes are explained by 40 +/- 15% type 1-3 collagen loss in the interstitial substance. Severe forms of GP in patients with JHM were observed in 84%. 52.4% females with JHM developed severe GP within 3 years after delivery of a child. Most of the examinees carried undifferentiated congenital dysplasias. CONCLUSION: JHM is a criterion of CTD diagnosis.

Age-dependent iris abnormalities in collagen XVIII/endostatin deficient mice with similarities to human pigment dispersion syndrome.

PURPOSE: Collagen XVIII is expressed in ocular basement membranes (BMs) and inactivating mutations cause Knobloch syndrome, with several ocular abnormalities. In this study we investigated ocular structures in collagen XVIII/endostatin (Col18a1(-/-))-deficient mice to elucidate the role of this extracellular matrix component in the eye. METHODS: Eyes of Col18a1(-/-) and control mice were examined by light and transmission electron microscopy, laser scanning ophthalmoscopy, and fluorescence angiography. Immunohistochemical analysis of neuronal, epithelial, and immune cells in the eye was performed with antibodies against established cell markers. RESULTS: Col18a1(-/-) mice showed a disruption of the posterior iris pigment epithelial (IPE) cell layer with release of melanin granules. The BM of the posterior IPE was attached to the lens and the nonpigmented epithelium of the ciliary body, which was flattened in mutant mice. In aged mutant mice a severe thickening of the stromal iris BM zone was found, and pigmented cells migrated out of the iris and covered the retina along the inner limiting membrane (ILM), sometimes penetrating into the retina. These cells resembled iris clump cells, and immunohistochemistry demonstrated that they were macrophage-like cells. Furthermore, morphologically abnormal retinal vasculature was seen by fluorescence angiography. CONCLUSIONS: The abnormalities in the iris and ciliary body of Col18a1(-/-) mice demonstrate an important role of collagen XVIII for the function of ocular BMs. The absence of this collagen alters the properties of BMs and leads to severe defects in the iris, showing striking similarities to human pigment dispersion syndrome. In addition, loss of collagen XVIII creates changes that allow clump cells to migrate out of the iris. These cells have not been well characterized previously. In the current study we showed that they are macrophage-like cells and are able to penetrate the ILM in mutant mice. The disease mechanism of human pigment dispersion syndrome is not well understood, but Col18a1(-/-) mice may serve as a model and demonstrate the potential importance of alterations in extracellular matrix components in this disease.

Differentiation potential of primary myogenic cells derived from skeletal muscle of dystonia musculorum mice.

The dystonia musculorum (dt) mouse has a mutation in the gene encoding the cytoskeletal crosslinker protein bullous pemphigoid antigen 1 (Bpag1). These mice have perturbations in the cytoarchitecture of skeletal muscle. Bpag1 has been hypothesized to be involved in the maintenance rather than the establishment of the muscle cell architecture given that cytoskeletal disruptions are observed in the muscle tissue of post-natal dt mice. Not known is whether Bpag1-deficiency affects the proliferative and differentiation potential of myogenic cells. In the present investigation, we show that the growth rate of cultured primary myogenic cells derived from dt mice, as assessed by BrdU incorporation, is similar to that of myogenic cells derived from wild-type littermates. The myogenic differentiation potential of dt versus wild-type cells was monitored by examining the expression of myosin heavy chain by immunofluorescence, and by analyzing the expression profiles of myogenic regulatory factors and myogenic differentiation markers by RT-PCR. In all instances, both dt and wild-type myogenic cells displayed a similar differentiation profile. Furthermore, the absence of any observable differences in the proliferation and differentiation rates of dt and wild-type cells was not due to an overexpression of plectin, another crosslinker protein, in dt cells. Together, these findings demonstrate that the early phases of myogenic differentiation occur independently of Bpag1.

Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis.

Obesity is more linked to vascular disease, including atherosclerosis and restenotic change, after balloon angioplasty. The precise mechanism linking obesity and vascular disease is still unclear. Previously we have demonstrated that the plasma levels of adiponectin, an adipose-derived hormone, decreases in obese subjects, and that hypoadiponectinemia is associated to ischemic heart disease. In current the study, we investigated the in vivo role of adiponectin on the neointimal thickening after artery injury using adiponectin-deficient mice and adiponectin-producing adenovirus. Adiponectin-deficient mice showed severe neointimal thickening and increased proliferation of vascular smooth muscle cells in mechanically injured arteries. Adenovirus-mediated supplement of adiponectin attenuated neointimal proliferation. In cultured smooth muscle cells, adiponectin attenuated DNA synthesis induced by growth factors including platelet-derived growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), basic fibroblast growth factor, and EGF and cell proliferation and migration induced by HB-EGF. In cultured endothelial cells, adiponectin attenuated HB-EGF expression stimulated by tumor necrosis factor alpha. The current study suggests an adipo-vascular axis, a direct link between fat and artery. A therapeutic strategy to increase plasma adiponectin should be useful in preventing vascular restenosis after angioplasty.

Osteogenesis imperfecta no adulto e resposta ao alendronato / Osteogenesis imperfecta in adult and alendronate response

A Osteogênese Imperfecta (OI) é um distúrbio hereditário do tecido conjuntivo, devido a um defeito qualitativo ou quantitativo do colágeno tipo I. Osteopenia, fraturas recorrentes e deformidades ósseas são as principais características da doença. Alguns pacientes também apresentam escleras azuladas. Os bisfosfonatos parecem constituir terapêutica eficiente em crianças, mas há poucos dados sobre o uso dessas drogas em adultos com 0I. Descrevemos o caso de uma paciente de trinta anos com 01 e múltiplas fraturas até a puberdade. Durante a primeira gestação as dores ósseas retornaram, piorando após o parto. Os marcadores bioquímicos sugeriam altas taxas de remodelação óssea, sendo iniciado alendronato sádico 10mg ao dia. Em poucos meses houve melhora das dores ósseas. Após o primeiro ano, a densidade mineral óssea aumentou em 10,8 por cento na coluna lombar (CL) e 2,3 por cento no coro femural (CF). No final do terceiro ano, o ganho total foi de 21,70;0 em CL e 10,9 por cento em CF. Nossos dados sugerem que o alendronato seja boa opção terapêutica em adultos com Osteogenesis Imperfecta.

Ligation of CD40 onvascular smooth muscle cells mediates loss of interstitial collagen via matrix metalloproteinase activity.

Interstitial collagen constitutes the predominant structural component of the fibrous cap of atherosclerotic plaque. The balance between synthesis and degradation of this extracellular matrix protein probably determines plaque stability and hence the tendency for plaque rupture. The CD40/CD40L signaling dyad has been implicated as an important regulatory pathway of collagen-degrading activity in atherosclerosis via the induction of matrix metalloproteinases (MMPs). However, the role of CD40 signaling in the synthesis of interstitial collagen and thus in the overall rate of collagen turnover has remained unknown. We demonstrate here that CD40 ligation on cultured human vascular smooth muscle cells (SMCs) diminishes the detectable content of de novo synthesized interstitial procollagens. Notably, the loss of collagen is not accompanied by a reduction in collagen transcript expression but can be prevented by MMP inhibition. These data demonstrate that CD40 signaling in human vascular SMC shifts interstitial collagen turnover towards the loss of this extracellular matrix protein by accelerating its degradation without concomitantly diminishing its synthesis. Thus, CD40/CD40L interactions might play a key role in rendering atheromatous lesions prone to rupture.

The role of type III collagen in family members of patients with abdominal aortic aneurysms.

OBJECTIVES: type III collagen is responsible for the tensile strength of the aorta-wall. To determine if genetic defect in the type III collagen production is associated with familial clustering of AAA. METHODS: fifty-six patients with AAA and 82 first-degree family members participated. The medical and family histories were obtained. All these relatives were screened by ultrasound for AAA. In 58 relatives of 20 families, skin biopsies were taken for protein analysis to measure type III collagen production in cultured fibroblasts. RESULTS: only one new AAA was detected in a brother of a patient. Four other relatives were already known with AAA. Three AAA patients had a type III collagen deficiency, but type III collagen was normal in all family members. CONCLUSION: type III collagen deficiency does not appear to be an aetiological factor in the development of AAA.