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PubMed2003

Investigation of mechanical behavior of articular cartilage by fibril reinforced poroelastic models.

The fibril reinforced poroelastic models have been found successful in describing some mechanical behaviors of articular cartilage in unconfined compression that were not understood previously, including the strong and nonlinear transient response, the strain-magnitude and strain-rate dependent cartilage stiffness and the depth-varying stresses and strains. It has been demonstrated that a better description for the mechanical behavior of cartilage is obtained by introducing a fibrillar matrix into a poroelastic model, in addition to the nonfibrillar matrix and water. This paper reports the development of the nonlinear fibril reinforced homogeneous and nonhomogeneous models and further explores the potentials of the models for investigation of cartilage mechanical response. Some comments are made in regard to further applications of the models and improved accuracy of the material representation.

Biomechanical Phenomena↗
PubMed2004

TGF-beta1 overexpression: a mechanism of diastolic filling dysfunction in the aged population.

The prevalence of cardiovascular disease in the United States dramatically increases with age. A hallmark feature of the aged myocardium is increased fibrosis resulting in diastolic dysfunction. Moreover, the survival of patients subsequent to a myocardial infarction is inversely related to age because of a certain extent to maladaptive remodeling mediated by cardiac fibroblasts. Our hypothesis is that cardiac fibroblast (CF) dysfunction results in overexpressed TGF-beta1 leading to increased cardiac collagen content in the aged population. TGF-beta1 stimulates the synthesis of the extracellular matrix proteins, including collagen in the cardiac tissues. The RT-PCR analysis of mRNA expression of TGF-beta1 of the CF was increased by 43% in the aged mice as compared to the younger. The stiffness of the left ventricle is expressed with the slope of the end-diastolic pressure-volume relationship parameter, beta (mmHg/microL). In a mouse model, we demonstrated that beta was 0.30 +/- 0.05 in the young as compared to 0.52 +/- 0.10 in the aged (p < .05). The ventricular stiffness was associated with the myocardial collagen content; namely, young versus the aged was 9.5 +/- 4.0 as compared to 16.4 +/- 2.3% of total protein, respectively (p < .05). In conclusion, the gene structure-function relationships support our hypothesis that cardiac fibroblast disregulation contributes to diastolic filling dysfunction in elderly persons. These data provide a potential contributory mechanism for diastolic dysfunction that may be vital in caring for the aged open-heart surgical patient.

Age Factors↗
PubMed2004

Static compression induces zonal-specific changes in gene expression for extracellular matrix and cytoskeletal proteins in intervertebral disc cells in vitro.

Compressive stimuli associated with weight-bearing and loading of the intervertebral disc are believed to be important regulators of disc cell metabolism. In this study, changes in gene expression levels for extracellular matrix and cytoskeletal proteins were quantified in disc cells in an alginate culture system subjected to static unconfined compression (25% compressive strain) after different time periods (2, 18 and 30 h). Differences in gene expression were observed between anulus fibrosus and nucleus pulposus cells following static compression for the matrix proteins studied here. Anulus fibrosus cells responded to mechanical deformation at the 30-h time point, with increasing gene expression for types I and II collagen, aggrecan, biglycan, decorin and lumican. In contrast, nucleus pulposus cells were not responsive to mechanical loading with changes in gene expression for these matrix proteins at any time. Our results also show that anulus fibrosus cells, but not nucleus pulposus cells, responded to static compression with increased expression of vimentin mRNA as well as increased polymerization of vimentin subunits. The results of the current study illustrate that fibrochondrocytes of the anulus fibrosus may regulate biosynthesis at the transcriptional level following mechanical deformation in an alginate construct. In contrast, the biological response of nucleus pulposus cells to these same stimuli is not detectable. These differences may be attributed to the presence of a notochordal cell population in the immature nucleus pulposus studied here, with a more diffuse and stiff cytoskeleton that may restrict deformations or shape changes upon compressive loading.

Animals↗
PubMed1995

Effect of perfusion pressure on diastolic stress-strain relations of isolated rat papillary muscle.

The effect of perfusion on diastolic muscle properties was investigated in six isolated right ventricular papillary muscles from rat hearts perfused with a crystalloid solution via the septal artery. Stress-strain relations were obtained at different perfusion pressures. Increased perfusion pressure caused an increase of stress at large strains but a decrease of stress at low strains. Thus stress-free strain increased with increasing perfusion pressure. Stress-strain relations of a given muscle at different perfusion pressures (range 12-122 cmH2O) intersected at a single "crossover" strain. Muscle stiffness, defined as the slope of the stress-strain relation, increased at all strains. Muscle diameter measurements indicated that the observed changes of the stress-strain relation occurred in association with vascular filling rather than with formation of edema. To explain the findings, the papillary muscle was modeled by two parallel compartments: muscle cells (together with the extracellular matrix) and vasculature. Perfusion was assumed to have an effect on the axial vascular properties but not on muscle cells. Combination of the stress-strain data of the muscle compartment and the vascular compartment (taken from literature) predicted stress-strain relations similar to those obtained in our perfused papillary muscles. We conclude that increased muscle stiffness at increased perfusion pressure is mainly caused by pressure-dependent changes in mechanical behavior of the vascular compartment.

Animals↗
PubMed2005

Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals.

BACKGROUND: Aortic stiffness is a marker of cardiovascular disease and an independent predictor of cardiovascular risk. Although an association between inflammatory markers and increased arterial stiffness has been suggested, the causative relationship between inflammation and arterial stiffness has not been investigated. METHODS AND RESULTS: One hundred healthy individuals were studied according to a randomized, double-blind, sham procedure-controlled design. Each substudy consisted of 2 treatment arms, 1 with Salmonella typhi vaccination and 1 with sham vaccination. Vaccination produced a significant (P<0.01) increase in pulse wave velocity (at 8 hours by 0.43 m/s), denoting an increase in aortic stiffness. Wave reflections were reduced significantly (P<0.01) by vaccination (decrease in augmentation index of 5.0% at 8 hours and 2.5% at 32 hours) as a result of peripheral vasodilatation. These effects were associated with significant increases in inflammatory markers such as high-sensitivity C-reactive protein (P<0.001), high-sensitivity interleukin-6 (P<0.001), and matrix metalloproteinase-9 (P<0.01). With aspirin pretreatment (1200 mg PO), neither pulse wave velocity nor augmentation index changed significantly after vaccination (increase of 0.11 m/s and 0.4%, respectively; P=NS for both). CONCLUSIONS: This is the first study to show through a cause-and-effect relationship that acute systemic inflammation leads to deterioration of large-artery stiffness and to a decrease in wave reflections. These findings have important implications, given the importance of aortic stiffness for cardiovascular function and risk and the potential of therapeutic interventions with antiinflammatory properties.

Adult↗
PubMed2005

Rapid establishment of chemical and mechanical properties during lamellar bone formation.

The development of prophylaxes and treatments of bone diseases that can effectively increase the strength of bone as a structure necessitates a better understanding of the time course by which chemical properties define the stiffness of the material during primary and secondary mineralization. It was hypothesized that these processes would be relatively slow in the actively growing skeleton. Seven-week-old Sprague-Dawley female rats (n = 8) were injected with multiple fluorochrome labels over a time span of 3 weeks and killed. Chemical and mechanical properties of the tibial mid-diaphysis were spatially characterized between the endocortical and periosteal surface by in situ infrared microspectroscopy and nanoindentation. The phosphate-to-protein ratio of bone 2-6 days old was 20% smaller at the periosteal surface and 22% smaller at the endocortical surface (P < 0.05 each) compared to older intracortical regions. The ratios of carbonate to protein, crystallinity, type A/type B carbonate, collagen cross-linking, and bone elastic modulus did not differ significantly between bone 2-6, 10-14, and 8-22 days old and intracortical regions. Intracortical properties of 10-week-old rats, except for the carbonate-to-protein ratio which was 23% smaller (P < 0.01), were not significantly different from intracortical matrix properties of young adult rats (5 months, n = 4). Spatially, the phosphate-to-protein ratio (R(2) = 0.33) and the phosphate-to-carbonate ratio (R(2) = 0.55) were significantly correlated with bone material stiffness, while the combination of all chemical parameters raised the R(2) value to 0.83. These data indicate that lamellar bone has the ability to quickly establish its mechanical and chemical tissue properties during primary and secondary mineralization even when the skeleton experiences rapid growth.

Animals↗
PubMed2001

Control of pH alters the type of cross-linking produced by 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) treatment of acellular matrix vascular grafts.

Carbodiimide cross-linking of bioprosthetic materials has been shown to provide tissue stabilization equivalent to that of glutaraldehyde cross-linking, but without the risk of the release of unreacted or depolymerized cytotoxic reagent after implantation. In this study, the effects of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) treatment on acellularized ovine carotid arteries were studied under two different pH conditions: (i) pH controlled at an optimal value of 5.5; and (ii) a simpler, but industrially significant, uncontrolled pH system. A multimode approach was employed involving biochemical assays, thermomechanical, tensile, and shear mechanical testing, and in vitro enzyme degradation analyses. EDC treatment decreased the hoop tangent modulus of acellular matrix (ACM) arterial grafts measured at 20 kPa of stress regardless of pH control. Extensibility of ACM arterial grafts measured at 20 kPa of stress was reduced after EDC treatment with pH control only. In contrast, shear stiffness of ACM arterial grafts increased to a greater degree under cross-linking without pH control (21 x compared to 14 x with pH control). Thermomechanical analyses revealed that EDC cross-linking with pH control also increased the collagen denaturation temperature of ACM arteries to a greater degree (a rise of 24.3 +/- 0.6 degrees C vs. 21.7 +/- 0.7 degrees C for no pH control), whereas cross-linking without pH control consumed a larger amount of lysine residues after 3 h of treatment. Most interestingly, both EDC treatments were equally effective in stabilizing ACM arteries against multiple degradative enzymes in vitro. The observed differences between EDC treatments under different pH conditions are attributed to differences in the location and types of the exogenous cross-links formed. The absence of pH control may have favored the formation of interfibrillar or intermolecular cross-links in collagen as well as involvement of other extracellular matrix components (proteoglycans and glycosaminoglycans). Furthermore, it may be emphasized that the location or type of cross-links differentially affected the mechanical behavior of treated materials without affecting the increase in resistance to enzymatic degradation.

Animals↗
PubMed1998

The dynamic response of L(2)/L(3) motion segment in cyclic axial compressive loading.

OBJECTIVE: The dynamic response and load sharing amongst passive elements of an L2-L3 motion segment during axial compressive cyclic loading was investigated. DESIGN: A validated viscoelastic nonlinear finite element model of L2-L3 was used for a detailed stress/strain analysis during axial cyclic loading. BACKGROUND: The repetitive loading of the spine has been implicated as a risk factor in developing low back disorders. However, the quantitative description of injury mechanisms and the internal load sharing have been lacking. METHODS: The applied cyclic axial compressive loading was controlled, peak to peak, from 600 to 1000 N at 0.5 Hz for 15 cycles. The stress/strain and strain energy density of various elements were quantified and the effects of cyclic loading on these parameters were investigated. RESULTS: The axial stiffness of the motion segment decreased, while intradiscal pressure (IDP) and the strain in anulus fibers of the outermost lamella increased. The axial stresses of outer lamellae in the anulus matrix reduced, in contrast to the increased strain at the endplate. CONCLUSIONS: The load sharing amongst the passive elements of the motion segment changed. The response of the motion segment to the same external axial load depends on the history of loading. The anulus fibers in the innermost layer were slack due to compression, hence not at risk of failure. The loss of disc height and increased disc bulge led to higher strain in anulus fibers of outermost layer. In future, more complex loading conditions with a longer duration should be considered.

Journal Article↗
PubMed2000

Cardiac fibrosis in mice lacking brain natriuretic peptide.

Cardiac fibrosis, defined as a proliferation of interstitial fibroblasts and biosynthesis of extracellular matrix components in the ventricles of the heart, is a consequence of remodeling processes initiated by pathologic events associated with a variety of cardiovascular disorders, which leads to abnormal myocardial stiffness and, ultimately, ventricular dysfunction. Brain natriuretic peptide (BNP) is a cardiac hormone produced primarily by ventricular myocytes, and its plasma concentrations are markedly elevated in patients with congestive heart failure and acute myocardial infarction. However, its precise functional significance has been undefined. In this paper, we report the generation of mice with targeted disruption of BNP (Nppb(-/-) mice). We observed multifocal fibrotic lesions in the ventricles from Nppb(-/-) mice. No signs of systemic hypertension and ventricular hypertrophy are noted in Nppb(-/-) mice. In response to ventricular pressure overload, focal fibrotic lesions are increased in size and number in Nppb(-/-) mice, whereas no focal fibrotic changes are found in wild-type littermates (Nppb(+/+) mice). This study establishes BNP as a cardiomyocyte-derived antifibrotic factor in vivo and provides evidence for its role as a local regulator of ventricular remodeling.

Animals↗
PubMed2005

The role of shape in determining molecular motions.

We examined the role of molecular shape in determining the patterns of low-frequency deformational motions of biological macromolecules. The low-frequency subspace of eigenvectors in normal mode analysis was found to be robustly similar upon randomization of the Hessian matrix elements as long as the structure of the matrix is maintained, which indicates that the global shape of molecules plays a more dominant role in determining the highly anisotropic low-frequency motions than the absolute values of stiffness and directionality of local interactions. The results provided a quantitative foundation for the validity of elastic normal mode analysis.

Biopolymers↗
PubMed1999

[Rigidity of large arteries and cardiovascular risk. epidemiological aspects and genetic determinants].

Most of the morbid events due to hypertension and other risk factors are related to alterations of the large arteries of the brain, the heart or the kidney. Historically large arteries have been considered as passive conduits of blood, and physicians, surgeons and pathologists were mainly interested on their anatomical lesions such as rupture, stenosis, aneurysm, or thrombosis. However we know that large arteries are not passive conduit tubes but are characterized by elastic properties and are able to synthesize many vasoactive substances. These properties make the arterial wall a major modulator of the blood pressure and more generally of the cardiovascular regulation. Aging, environmental and genetic factors are responsible for structural and functional changes of the arterial wall media (hypertrophy, extracellular matrix accumulation, calcium deposits) and of the vascular endothelium (decrease in the release of vasodilators and increased synthesis of vasoconstrictors), all that leading to a diminution of elasticity and increased stiffness. The alteration of large arteries elasticity has deleterious effects on the heart upstream being responsible for an inadequate increase in systolic pressure and a relative decrease in aortic diastolic pressure at any given value of mean arterial pressure. The elevation in systolic pressure causes a disproportionate increase in end-systolic stress, which is the principal hemodynamic factor which promotes the development of cardiac hypertrophy, increased ventricular oxygen consumption, and left ventricular hypertrophy and can compromise capacity for coronary perfusion. Clinical and epidemiological studies have raised the possibility that subjects with stiffer arteries have wide pulse pressure, and that stiffening of large arteries is associated with excess morbidity and mortality independently of mean blood pressure. In addition to its etiologic role in cardiovascular disease, increased arterial stiffness may serve as an early marker for the diagnosis of asymptomatic atherosclerotic lesions, or for the evaluation of the severity of these lesions. In this review we report data from clinical, epidemiological and genetic studies, suggesting that arterial stiffness may be considered as a significant marker and/or an independent cardiovascular risk factor. This new concept should lead physicians to evaluate arterial stiffness for the prognosis and treatment of cardiovascular patients.

Aldosterone↗
PubMed2004

Influence of the extracellular matrix on the regulation of cardiac fibroblast behavior by mechanical stretch.

Fibroblasts are responsible in large part for production, organization, and turnover of the extracellular matrix (ECM), thereby regulating the fibrotic content of the heart. Excessive fibrosis, which has been associated with certain forms of hemodynamic overload such as hypertension, is thought to result in increased ventricular chamber stiffness, and eventual heart failure. As such, the role of mechanical stretch in regulating fibroblast activity is crucial to our understanding of healthy and diseased hearts. However, little is known about the effects of alterations in the composition of the ECM in regulating mechanotransduction in cardiac fibroblasts. In order to address this question, rat cardiac fibroblasts were cultured on silastic membranes coated with different ECM substrates, and cyclically stretched for various durations. Experiments were designed to assess the activation of signaling pathways, as well as changes in collagen production, cellular proliferation, and morphology. Mitogen activated protein kinase (MAP kinase) was most rapidly activated, and collagen I expression was most abundant, in cells stretched on randomly organized collagen, and uncoated charged membranes. Regardless of the nature of the ECM substrate, stretched cells decreased proliferation, however, this effect was most marked in cells stretched on randomly organized collagen. Finally, cells stretched on all ECM substrates increased their surface area, but this was observed most significantly in cells adherent to aligned collagen, randomly organized collagen, and uncoated, charged membranes. Taken together, these results suggest cardiac fibroblasts may differentially interpret a mechanical stimulus, in terms of both signal transduction, and specific long-term events such as gene transcription, based on the composition and organization of the ECM.

Animals↗
PubMed1992

The effects of selective matrix degradation on the short-term compressive properties of adult human articular cartilage.

The effects of proteoglycan and collagen digestion on the transient response of human articular cartilage when tested in unconfined compression were determined. Small cylindrical specimens of cartilage, isolated from the femoral head of the hip joint and from the femoral condyles of the knee joint, were subjected to a suddenly applied compressive load using a test apparatus designed to yield a transient oscillatory response. From this response values of the elastic stiffness and the viscous damping coefficient were determined. Cathepsin D and cathepsin B1 were used to digest the proteoglycan in some specimens, while in other specimens leukocyte elastase was used to attack the non-helical terminal regions of the Type II tropocollagen molecules and possibly the Type IX collagen molecule and thereby disturb the integrity of the collagen mesh. The results showed that proteoglycan digestion alone reduced the viscous damping coefficient but it did not significantly alter the elastic stiffness as determined from the oscillatory response. In contrast, the action of elastase reduced both the damping coefficient and the elastic stiffness of the cartilage. The results demonstrated the role of proteoglycans in regulating fluid transport in cartilage and hence controlling the time-dependent viscous properties. The elastic stiffness was shown to be dependent on the integrity of the collagen fibre network and not on the proteoglycans.

Aged↗
PubMed2006

Effect of spatial architecture on cellular colonization.

The spatial cell-material interaction remains vital issue in forming biodegradable scaffolds in Tissue Engineering. In this study, to understand the influence of spatial architecture on cellular behavior, 2D and 3D chitosan scaffolds of 50-190 kD and >310 kD MW were synthesized through air drying and controlled rate freezing/lypohilization technique, respectively. In addition, chitosan was emulsified with 19, 76, and 160 kD 50:50 poly lactide-co-glycolide (PLGA) using 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) as stabilizer. 2D and 3D scaffolds were formed by air drying and lyophilization as before. Tensile and compressive properties of films and scaffolds were analyzed in wet conditions at 37 degrees C. Alterations in the cell spreading, proliferation, and cytoskeletal organization of human umbilical vein endothelial cells (HUVECs) and mouse embryonic fibroblasts (MEFs) were studied. These results showed that the formed 3D chitosan scaffolds had interconnected open pore architecture (50-200 microm size). HUVECs and MEFs had reduced spreading areas and circular morphology on 2D chitosan membranes compared with 3D chitosan scaffolds. The fluorescence photomicrographs for actin (using Alexa Fluor 488 phalloidin) and cytoplasm staining (using carboxyfluorescein diacetate-succinimidyl ester) demonstrated that the cells spread within 3D chitosan matrix. 2D and 3D emulsified chitosan and chitosan/PLGA scaffolds reduced the spreading of HUVECs and MEFs even further. Proliferation results, analyzed via MTT-Formazan assay and BrdU uptake assay, correlated with the spreading characteristics. The reductions in cell spreading area on emulsified surfaces were not detrimental to the viability and endocytic activity but to proliferation. The observed alterations in cellular colonization are in part due to the substrate stiffness and surface topography. In summary, these results suggest a significant influence of spatial architecture on cellular colonization.

Cell Culture Techniques↗
PubMed1994

Myocardial collagen matrix remodeling and congestive heart failure.

In chronic heart failure, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of primary clinical interest. In the pressure or volume overloaded heart, hypertrophic growth of the myocardium includes the enlargement of cardiac myocytes--an adaptation governed by ventricular loading. Nonmyocyte cell growth involving cardiac fibroblast may also occur but not primarily regulated by the hemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure. In vivo and in vitro studies suggest that the effector hormones, angiotensin II and aldosterone, of the RAAS are primarily involved in regulating the structural remodeling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and aldosterone have been shown to stimulate collagen synthesis while angiotensin II additionally inhibits matrix metalloproteinase 1 activity, which is the key enzyme for interstitial collagen degradation in the myocardium. These observations may serve as rationale why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy in congestive heart failure in patients with hypertensive heart disease, post-myocardial infarction or with dilated cardiomyopathy.

Cardiomegaly↗
PubMed1995

The renin-angiotensin-aldosterone system and myocardial collagen matrix remodelling in congestive heart failure.

In chronic heart failure, various regulatory systems including the Frank-Starling mechanism, the neuro-hormonal response, cardiac growth and peripheral oxygen delivery may be operative. Recently, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth has drawn clinical interest. In the pressure-or volume-overloaded heart, the development of myocyte growth is primarily dependent on ventricular loading. Non-myocyte cell growth involving cardiac fibroblasts may also occur but this is not primarily regulated by the haemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the progression of symptomatic heart failure. The effector hormones of the RAAS, angiotensin II (AngII) and aldosterone (Aldo), appear to be primarily involved in promoting the adverse structural remodelling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, AngII and Aldo have been shown to stimulate collagen synthesis while AngII additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for degradation of fibrillar collagen in the cardiac interstitium, leading to excessive collagen accumulation. These findings may serve as rationale as to why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy beyond the effect of simply unloading the heart in patients with congestive heart failure.

Adult↗
PubMed2004

Osteoclast deficiency results in disorganized matrix, reduced mineralization, and abnormal osteoblast behavior in developing bone.

UNLABELLED: Studies of the influence of the osteoclast on bone development, in particular on mineralization and the formation of the highly organized lamellar architecture of cortical bone by osteoblasts, have not been reported. We therefore examined the micro- and ultrastructure of the developing bones of osteoclast-deficient CSF-1R-nullizygous mice (Csf1r(-/-) mice). INTRODUCTION: Colony-stimulating factor-1 receptor (CSF-1R)-mediated signaling is critical for osteoclastogenesis. Consequently, the primary defect in osteopetrotic Csf1r(-/-) mice is severe osteoclast deficiency. Csf1r(-/-) mice therefore represent an ideal model system in which to investigate regulation by the osteoclast of osteoblast-mediated bone formation during development. MATERIALS AND METHODS: Bones of developing Csf1r(-/-) mice and their littermate controls were subjected to X-ray analysis, histological examination by light microscopy and transmission electron microscopy, and a three-point bending assay to test their biomechanical strength. Bone mineralization in embryonic and postnatal bones was visualized by double staining with alcian blue and alizarin red. Bone formation by osteoblasts in these mice was also examined by double-calcein labeling and in femoral anlagen transplantation experiments. RESULTS AND CONCLUSIONS: Frequent spontaneous fractures and decreased strength parameters (ultimate load, yield load, and stiffness) in a three-point bending assay showed the biomechanical weakness of long bones in Csf1r(-/-) mice. Histologically, these bones have an expanded epiphyseal chondrocyte region, a poorly formed cortex with disorganized collagen fibrils, and a severely disturbed matrix structure. The mineralization of their bone matrix at secondary sites of ossification is significantly reduced. While individual osteoblasts in Csf1r(-/-) mice have preserved their typical ultrastructure and matrix depositing activity, the layered organization of osteoblasts on the bone-forming surface and the direction of their matrix deposition toward the bone surface have been lost, resulting in their abnormal entrapment by matrix. Moreover, we also found that (1) osteoblasts do not express CSF-1R, (2) the bone defects in Csf1r(-/-) embryos develop later than the development of osteoclasts in normal embryos, and (3) the transplanted Csf1r(-/-) femoral anlagen develop normally in the presence of wildtype osteoclasts. These results suggest that the dramatic bone defects in Csf1r(-/-) mice are caused by a deficiency of the osteoclast-mediated regulation of osteoblasts and that the osteoclast plays an important role in regulating osteoblastic bone formation during development, in particular, in the formation of lamellar bone.

Animals↗
PubMed2002

Genotypic and phenotypic expression of vocal fold polyps and Reinke's edema: a preliminary study.

Although a great deal of research exists regarding lamina propria composition, no report exists that relates gene expression in benign laryngeal lesions to phenotypic markers. In this study, messenger RNA profiles for extracellular matrix proteins--procollagen I, collagenase, elastase, fibronectin, fibromodulin, decorin, hyaluronic acid synthase 2, and hyaluronidase--were completed on 5 polyps and 4 Reinke's edema specimens. These genotypic profiles were correlated to a videostroboscopic parameter of mucosal wave stiffness, which was used as a measurement of phenotypic expression. Polyps, characterized by stiffer mucosal waves, had higher levels of gene expression, whereas stiffer mucosal wave scores for Reinke's edema were associated with lower gene activity levels. This study supports the hypothesis that there is a relationship between genotypic expression found in polyps and Reinke's edema and phenotype as defined by a loss of or a decreased mucosal wave. The study also gives clues as to the proteins responsible for the phenotype.

Base Sequence↗