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PubMed1999

The molecular basis of the solution properties of hyaluronan investigated by confocal fluorescence recovery after photobleaching.

Hyaluronan (HA) is a highly hydrated polyanion, which is a network-forming and space-filling component in the extracellular matrix of animal tissues. Confocal fluorescence recovery after photobleaching (confocal-FRAP) was used to investigate intramolecular hydrogen bonding and electrostatic interactions in hyaluronan solutions. Self and tracer lateral diffusion coefficients within hyaluronan solutions were measured over a wide range of concentrations (c), with varying electrolyte and at neutral and alkaline pH. The free diffusion coefficient of fluoresceinamine-labeled HA of 500 kDa in PBS was 7.9 x 10(-8) cm(2) s(-1) and of 830 kDa HA was 5.6 x 10(-8) cm(2) s(-1). Reductions in self- and tracer-diffusion with c followed a stretched exponential model. Electrolyte-induced polyanion coil contraction and destiffening resulted in a 2.8-fold increase in self-diffusion between 0 and 100 mM NaCl. Disruption of hydrogen bonds by strong alkali (0.5 M NaOH) resulted in further larger increases in self- and tracer-diffusion coefficients, consistent with a more dynamic and permeable network. Concentrated hyaluronan solution properties were attributed to hydrodynamic and entanglement interactions between domains. There was no evidence of chain-chain associations. At physiological electrolyte concentration and pH, the greatest contribution to the intrinsic stiffness of hyaluronan appeared to be due to hydrogen bonds between adjacent saccharides.

Animals↗
PubMed1987

Pattern of connective tissue development in swine pulmonary vasculature by immunolocalization.

Light microscopic immunolocalization studies were carried out on lung tissue from eight newborn and four adult pigs using antibodies to six extracellular matrix components. Antibodies to fibronectin, collagen type IV, and laminin localized on the same structures in adult and newborn lungs. By contrast, antibodies to the interstitial collagens (types I, III, and V) were less extensively localized in the newborn than in the adult, particularly those to type I because the fibres on which they localized in the newborn were thin and sparse. At all ages, antibodies to collagen types III and V co-localized on type I fibres and also on thin individual fibres which formed networks, more dense in the adult than in the newborn. At all ages, anti-type III collagen antibodies also localized on smooth muscle cells. In the adult, but not in the newborn, anti-type I and type V collagen antibodies localized on the connective tissue around the smooth muscle cells in the pulmonary arterial media and vein wall. The dominance of collagen type III suggests greater plasticity in the newborn pulmonary vasculature, which helps explain the recently described rapid changes in arterial wall structure which constitute adaptation to extrauterine life. The postnatal increase in collagen type I helps explain the documented postnatal increase in structural stiffness of the pulmonary arteries.

Aging↗
PubMed2007

Bone morphogenetic proteins-signaling plays a role in tendon-to-bone healing: a study of rhBMP-2 and noggin.

BACKGROUND: Successful anterior cruciate ligament reconstruction requires secure healing between tendon and bone. HYPOTHESIS: Bone morphogenetic protein-signaling plays an important role in tendon-to-bone healing. rhBMP-2, a powerful osteoinductive agent, can improve tendon-bone interdigitation. STUDY DESIGN: Controlled laboratory study. METHODS: The study was designed in 2 phases: Phase I consisted of a dose-response study where 21 New Zealand White rabbits underwent bilateral anterior cruciate ligament reconstructions. Rabbits received either rhBMP-2 (11.5, 50, or 115 microg) or noggin (10, 15, 30, or 100 ng) (a potent bone morphogenetic proteins inhibitor) delivered in an injectable calcium phosphate matrix. Animals were sacrificed at 2 weeks and histomorphometric analyses were performed. In phase II, 60 rabbits underwent bilateral anterior cruciate ligament reconstructions and were assigned to 3 groups: rhBMP-2 (115 microg), noggin (30 ng) in a calcium phosphate carrier, and calcium phosphate carrier alone. Animals were sacrificed at 2, 4, and 8 weeks and histomorphometric and biomechanical analyses were performed. RESULTS: rhBMP-2 treatment led to a significant increase in the width of new bone formation at the tendon-bone interface in a dose-dependent fashion (0.24-0.35 mm vs 0.13-0.16 mm in controls). All dosages of noggin inhibited new bone formation (0.06-0.1 mm vs 0.15-0.16 mm in controls); however, there was no dose-dependent effect in the concentrations studied. In the phase II study, rhBMP-2 resulted in a significant increase in new bone formation (81%, 89%, and 113%) at increasing time periods compared with controls. Tunnel diameters in the rhBMP-2 group were significantly smaller (15%-45%) than in the carrier group. The negative effect of noggin was not sustained, as new bone formation increased with time. The rhBMP-2 group demonstrated significantly increased stiffness at 8 weeks, while there was no significant difference in ultimate tensile load when compared with the other 2 groups. CONCLUSION: rhBMP-2 demonstrated a strong, positive dose-dependent effect on osteointegration at the tendon-bone junction. In contrast, noggin decreased osteointegration. No tunnel widening was detected with rhBMP-2 using the calcium phosphate carrier. CLINICAL RELEVANCE: Further studies are needed to investigate the potential clinical application of enhancing healing and decreasing recovery time using bone morphogenetic proteins in soft tissue ligament reconstruction.

Animals↗
PubMed2004

Effects of hypophysectomy and recombinant human growth hormone on material and geometric properties and the pre- and post-yield behavior of femurs in young rats.

To study the musculoskeletal effects of hypophysectomy (Hx) and a partial replacement treatment with recombinant human growth hormone (rhGH) in rats, we determined the stiffness (elastic modulus, E) and volumetric BMD (vBMD) of cortical bone; the periosteal and endosteal perimeters, area and bending moment of inertia (xCSMI) of the cross sections, and the structural stiffness and pre- and post-yield strength of the femur diaphyses by pQCT and mechanical tests, and the gastrocnemius weight of rats that were either intact (n = 9) or Hx at 15 days of age (20). The latter were otherwise untreated (Hx controls, 4) or given 0.4 (8) or 2.0 (8) IU kg(-1) day(-1), s.c., of rhGH for 45 days starting 15 days after surgery. Hx delayed musculoskeletal development (gastrocnemius weight, bone geometric properties), thus affecting the diaphyseal stiffness and strength. It also reduced the cortical vBMD through an undefined mechanism, and increased the elastic modulus of cortical bone. The Hx also affected the correlation between bone geometric and material properties (xCSMI vs. E), suggesting an antianabolic interaction with the biomechanical control of bone modeling in response to strains caused by mechanical usage. As a result, Hx reduced the stiffness, post-yield, and ultimate strength of the diaphyses. These effects should reflect changes in bone tissue microstructure, perhaps associated with crack generation and progress, but unrelated to bone mineral mass. They are compatible with the induction of a delay in collagen turnover with associated increases in fibers' diameter and crystals' size that may have resulted from the suppression of some other hormones, such as thyroid, prolactin, or other hormones regulated by ACTH. The above doses of rhGH significantly but incompletely prevented the negative Hx effects on bone and muscle development (bone geometric properties, muscle mass). However, rhGH treatment failed to prevent the demineralizing and stiffening effect of Hx on bone tissue and the unusual effects on the post-yield strength (less clearly related to muscle development than the former). Consequently, rhGH treatment tended to preserve the natural relationship between muscle function and bone geometry but not bone strength. The effects of larger rhGH doses and the interaction of other hormones with the described effects remain to be investigated. Nevertheless, these findings would deserve special attention because they challenge the prevailing view that in endocrine-metabolic bone-weakening diseases the bone matrix always has a normal composition.

Aging↗
PubMed1999

Matrix metalloproteinase inhibition during the development of congestive heart failure : effects on left ventricular dimensions and function.

The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi, rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CHF, LV fractional shortening was reduced (19+/-1 versus 45+/-1%), and end-diastolic dimension increased (5.67+/-0.11 versus 3.55+/-0.05 cm), compared with baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shortening increased (25+/-2%) and the end-diastolic dimension was reduced (4.92+/-0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and was significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte length was increased with pacing CHF compared with controls (180+/-3 versus 125+/-4 microm, P<0.05) and was reduced in the CHF/MMPi group (169+/-4 microm, P<0.05). Basal-state myocyte shortening velocity was reduced with pacing CHF compared with controls (33+/-2 versus 66+/-1 microm/s, P<0.05) and was unchanged in the CHF/MMPi group (31+/-2 microm/s). Using an ex vivo assay system, myocardial MMP activity was increased with pacing CHF and was reduced with chronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dilation and reduced wall stress. These results suggest that increased myocardial MMP activity contributes to LV myocardial remodeling in developing CHF.

Animals↗
PubMed1996

Determination of collagen-proteoglycan interactions in vitro.

The objective of this study was to characterize the physical interactions of the molecular networks formed by mixtures of collagen and proteoglycan in vitro. Pure proteoglycan aggrecan solutions, collagen (type II) suspensions and mixtures of these molecules in varying proportions and concentrations were subjected to viscometric flow measurements using a cone-on-plate viscometer. Linear viscoelastic and non-Newtonian flow properties of these solutions and suspensions were described using a second-order statistical network theory for polymeric fluids (Zhu et al., 1991, J. Biomechanics 24, 1007-1018). This theory provides a set of material coefficients which relate the macroscopic flow behavior of the fluid to an idealized molecular network structure. The results indicated distinct differences between the flow properties of pure collagen suspensions and those of pure proteoglycan solutions. The collagen network showed much greater shear stiffness and more effective energy storage capability than the proteoglycan network. The relative proportion of collagen to proteoglycan is the dominant factor in determining the flow behavior of the mixtures. Analysis of the statistical network theory indicated that the collagen in a collagen-proteoglycan mixture enhances molecular interactions by increasing the amount of entanglement interactions and/or the strength of interaction, while aggrecan acts to reduce the number and/or strength of molecular interactions. These results characterize the physical interactions between type II collagen and aggrecan and provide some insight into their potential roles in giving articular cartilage its mechanical behavior.

Aggrecans↗
PubMed2003

A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2), surgically implanted with a matrix material, has been shown to induce bone formation and enhance fracture repair. The purpose of this investigation was to test the hypothesis that a single, local, percutaneous injection of rhBMP-2 would accelerate fracture-healing in a standard rat femoral fracture model. METHODS: Fractures were created, following intramedullary pinning, in the femora of 144 male Sprague-Dawley rats. The animals were divided into three groups of forty-eight each. Six hours after the fracture, one group received an injection of 80 micro g of rhBMP-2 in 25 micro L of buffer vehicle, one received an injection of 25 micro L of buffer vehicle alone, and one did not receive an injection. Twelve animals from each of these three groups were killed at one, two, three, and four weeks after treatment, and the femora were harvested for torsional biomechanical testing. An additional cohort of seventy-two animals, in which a fracture was also created, was divided into the same three treatment groups; six animals from each of these groups was killed at one, two, three, and four weeks; and the femora were processed for qualitative histological analysis. RESULTS: Torsional biomechanical testing indicated that the stiffness of the rhBMP-2-treated fractures was twice that of both control groups at the two, three, and four-week time-points. The strength of the rhBMP-2-treated fractures was 34% greater than that of the buffer-treated controls (p = 0.03) at three weeks and, at four weeks, was 60% and 77% greater than that of the buffer-treated controls and that of the untreated controls, respectively (p < 0.005). At four weeks, the stiffness and strength of the rhBMP-2-treated fractures were equal to those of the intact contralateral femora, whereas the buffer-treated and untreated fractures were significantly weaker than the intact femora. At two and three weeks, large areas of bone formation, typically spanning the fracture, were observed histologically in the rhBMP-2-treated sites. In contrast, the control fractures exhibited primarily soft cartilaginous callus at these time-points. By four weeks, remodeling of the hard callus and recorticalization were observed in the rhBMP-2-treated fracture sites, whereas cartilage and/or soft tissue was still present in the control fracture sites. CONCLUSIONS: These data demonstrate that a single, local, percutaneous injection of rhBMP-2 accelerates fracture repair in this rat femoral fracture model. This effect appears to result from a combination of the induction of bone formation at the fracture site and acceleration of the rate at which the fracture callus matures.

Animals↗
PubMed2001

Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats.

UNLABELLED: OBJECTIVES; We assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix. BACKGROUND: Although the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF. METHODS: Dahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group). RESULTS: High-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group. CONCLUSIONS: Long-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.

Amlodipine↗
PubMed1997

Role of glomerular mechanical strain in the pathogenesis of diabetic nephropathy.

Glomerular rigidity limits the glomerular expansion and mesangial cell (MC) stretch induced by variations in intracapillary pressure. In tissue culture, MC stretch stimulates synthesis of extracellular matrix components (ECM). Therefore, altered glomerular rigidity in diabetes may influence ECM accumulation by modulating the glomerular distention and MC stretch associated with glomerular hypertension. An ambient of high glucose concentration per se also enhances MC formation of ECM, possibly altering the cellular response to mechanical stretch. In this study, compliance was measured in isolated perfused glomeruli from streptozotocin-injected rats at four days (4d-D), five weeks (5w-D) and six months (6m-D) after induction of diabetes. In addition, collagen metabolism induced by stretch was investigated in MC cultured in 8 and 35 mM glucose concentrations. Glomerular compliance was normal in 5w-D rats and moderately increased in 4d-D (16%) and 6m-D animals (14%). As compared to static cultures. MC stretch increased total collagen synthesis (8 mM, 50%; 35 mM, 27%) and catabolism. However, while the fraction of newly formed collagen being catabolized increased in 8 mM-stretched cultures, in 35 mM-stretched it was unchanged. This resulted in marked increase in the net collagen accumulated in the incubation medium (4 vs. 24%) and cell layer 5 vs. 15%) only in the latter. In diabetes, the largely unaltered glomerular stiffness renders hypertension-induced MC stretch unopposed. More importantly, the accumulation of ECM caused by any degree of mechanical strain is greatly aggravated in a milieu of high glucose concentration.

Animals↗
PubMed2001

Roles of articular cartilage aging and chondrocyte senescence in the pathogenesis of osteoarthritis.

Osteoarthritis (OA), the disease characterized by joint pain and loss of joint form and function due to articular cartilage degeneration, is not an inevitable consequence of aging, but a strong association exists between age and increasing evidence of OA. Aging changes in articular cartilage that increase the risk of articular cartilage degeneration include fibrillation of the articular surface, decrease in the size and aggregation of proteoglycan aggrecans, increased collagen cross-linking and loss of tensile strength and stiffness. These alterations are most likely primarily the result of aging changes in chondrocyte function that decrease the ability of the cells to maintain the tissue including decreased synthetic activity, synthesis of smaller less uniform aggrecans and less functional link proteins and decreased responsiveness to anabolic growth factors. Our recent work suggests that the cause of the age-related loss of chondrocyte function may be progressive senescence of articular cartilage chondrocytes marked by a decline in mitotic activity, increased expression of the senescence-associated enzyme beta-galactosidase and erosion of telomere length. New efforts to prevent the development or progression of OA might include strategies that delay the onset of chondrocyte senescence or replace senescent cells.

Aggrecans↗
PubMed2005

Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion.

The morphology and cytoskeletal structure of fibroblasts, endothelial cells, and neutrophils are documented for cells cultured on surfaces with stiffness ranging from 2 to 55,000 Pa that have been laminated with fibronectin or collagen as adhesive ligand. When grown in sparse culture with no cell-cell contacts, fibroblasts and endothelial cells show an abrupt change in spread area that occurs at a stiffness range around 3,000 Pa. No actin stress fibers are seen in fibroblasts on soft surfaces, and the appearance of stress fibers is abrupt and complete at a stiffness range coincident with that at which they spread. Upregulation of alpha5 integrin also occurs in the same stiffness range, but exogenous expression of alpha5 integrin is not sufficient to cause cell spreading on soft surfaces. Neutrophils, in contrast, show no dependence of either resting shape or ability to spread after activation when cultured on surfaces as soft as 2 Pa compared to glass. The shape and cytoskeletal differences evident in single cells on soft compared to hard substrates are eliminated when fibroblasts or endothelial cells make cell-cell contact. These results support the hypothesis that mechanical factors impact different cell types in fundamentally different ways, and can trigger specific changes similar to those stimulated by soluble ligands.

Actins↗
PubMed2006

[An antidestructive effect of leflunomide in early rheumatoid arthritis].

AIM: To study effects of leflunomide on inflammatory and destructive processes in patients with early rheumatoid arthritis (RA). MATERIAL AND METHODS: The trial included 33 patients (27 females and 6 males) with a significant diagnosis of RA (A CR criteria) aged 19 to 60 years and duration of the disease from 6 months to 3 years (15.97 +/- 9.70 months). The activity of the inflammatory process and treatment efficacy were assessed by severity of the articular syndrome, duration of morning stiffness (DMS), pain and the disease activity (VAS), device examination, the disease activity by DAS28 indices, etc. The articular syndrome was assessed by the number of painful joints (NPJ), number of swollen joints (NSJ), etc. The functional status of the patient was evaluated by Keitel test, HAQ and hand grip. Calculations were made of erosive arthritis progression rate (EAPR) and joint fissure narrowing progression rate (FNPR). All the patients received leflunomide (100 mg/day for 3 days, then 20 mg/day). A 12-month course was finished by 14 patients, 4 patients were withdrawn because of side effects, the rest--by social causes. RESULTS: To the end of the trial leflunomide reduced NPJ by 84%, NSJ--by 95%, DMS--by 88%, articular pain by VAS--by 66%, the disease activity by VAS--by 70%. A positive trend in DAS28 criterium was observed (a significant suppression of RA activity after 1 month of therapy by 18%, after 4 months--by 39%, after 6 months--by 43%, by the end of the treatment--by 48%). For the initial 6 months EAPR was 0.50 +/- 0.67, for the following 6 months it lowered to 0.37 +/- 1.00, while FNPR decreased to 1.14 +/- 1.26 vs. 1.31 +/- 2 58 for initial 6 months. A positive change of the level of type 3 matrix metalloproteinase (a 20% and 16% by month 4 and to the end of the trial, respectively) was registered. CONCLUSION: A positive effect of leflunomide on RA inflammatory activity and progression rate of joint destruction was confirmed.

Adjuvants, Immunologic↗
PubMed1999

Marimastat in patients with advanced pancreatic cancer: a dose-finding study.

Patients with solid tumors, including carcinoma of the pancreas, express high levels of matrix metalloproteinases (MMP), and these enzymes are believed to be important for the growth, spread, and dissemination of most solid malignant tumors. Marimastat is the first orally available MMP inhibitor (MMPI) to be tested in humans and has been shown to inhibit the spread and growth of pancreatic cancer in animal models. The purpose of the present study was to define the toxicities, safety, and tolerance of various doses of marimastat and also to get an early indication of potential biologic activity in patients with advanced pancreatic cancer. The authors prospectively studied 64 patients with advanced carcinoma of the pancreas in whom standard treatments had failed. Eligible patients had a progressive rise in CA 19/9 levels of >25% over the 4-week period preceding their entry into the study. Patients were studied in groups of 8 to 10, with each group receiving escalating dosages ranging from 5 mg twice daily to 75 mg twice daily and 10 to 25 mg daily. Patients were considered for long-term (beyond 4 weeks) continuation treatment if clinical benefit, in the view of the investigator, was derived. Study endpoints were safety, tolerance, and changes in the rate of rise of CA 19/9, which were used as surrogate markers for disease progression. Marimastat was well tolerated. Musculoskeletal pain, stiffness, and tenderness emerged as dose-limiting toxicity. No other dose-related toxicities were observed. A reduced rate of rise of CA 19/9 was observed at dose levels of 5, 10, and 25 mg twice daily. The overall median survival was 160 days, with a 1-year survival of 21%. Marimastat was associated with an acceptable toxicity profile, and these preliminary data suggest that long-term oral administration is feasible and safe. Doses of 5, 10, and 25 mg twice daily were identified as the optimal doses to be tested in larger randomized studies.

Adult↗
PubMed2006

Murine model of the Ehlers-Danlos syndrome. col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages.

The most commonly identified mutations causing Ehlers-Danlos syndrome (EDS) classic type result in haploinsufficiency of proalpha1(V) chains of type V collagen, a quantitatively minor collagen that co-assembles with type I collagen as heterotypic fibrils. To determine the role(s) of type I/V collagen interactions in fibrillogenesis and elucidate the mechanism whereby half-reduction of type V collagen causes abnormal connective tissue biogenesis observed in EDS, we analyzed mice heterozygous for a targeted inactivating mutation in col5a1 that caused 50% reduction in col5a1 mRNA and collagen V. Comparable with EDS patients, they had decreased aortic stiffness and tensile strength and hyperextensible skin with decreased tensile strength of both normal and wounded skin. In dermis, 50% fewer fibrils were assembled with two subpopulations: relatively normal fibrils with periodic immunoreactivity for collagen V where type I/V interactions regulate nucleation of fibril assembly and abnormal fibrils, lacking collagen V, generated by unregulated sequestration of type I collagen. The presence of the aberrant fibril subpopulation disrupts the normal linear and lateral growth mediated by fibril fusion. Therefore, abnormal fibril nucleation and dysfunctional fibril growth with potential disruption of cell-directed fibril organization leads to the connective tissue dysfunction associated with EDS.

Alleles↗
PubMed2006

Decorin regulates assembly of collagen fibrils and acquisition of biomechanical properties during tendon development.

Tendon function involves the development of an organized hierarchy of collagen fibrils. Small leucine-rich proteoglycans have been implicated in the regulation of fibrillogenesis and decorin is the prototypic member of this family. Decorin-deficient mice demonstrate altered fibril structure and mechanical function in mature skin and tail tendons. However, the developmental role(s) of decorin needs to be elucidated. To define these role(s) during tendon development, tendons (flexor digitorum longus) were analyzed ultrastructurally from postnatal day 10 to 90. Decorin-deficient tendons developed abnormal, irregularly contoured fibrils. Finite mixture modeling estimated that the mature tendon was a three-subpopulation mixture of fibrils with characteristic diameter ranges. During development, in each subpopulation the mean diameter was consistently larger in mutant mice. Also, diameter distributions and the percentage of fibrils in each subpopulation were altered. Biomechanical analyses demonstrated that mature decorin-deficient tendons had significantly reduced strength and stiffness; however, there was no reduction in immature tendons. Expression of decorin and biglycan, a closely related family member, was analyzed during development. Decorin increased with development while biglycan decreased. Spatially, both had a comparable localization throughout the tendon. Biglycan expression increased substantially in decorin-deficient tendons suggesting a potential functional compensation. The accumulation of structural defects during fibril growth, a period associated with decorin expression and low biglycan expression, may be the cause of compromised mechanical function in the absence of decorin. Our findings indicate that decorin is a key regulatory molecule and that the temporal switch from biglycan to decorin is an important event in the coordinate regulation of fibrillogenesis and tendon development.

Animals↗
PubMed2002

Aging of myocardial collagen.

The objective of this article was to present a review of the collagen tissue of the heart muscle as a function of age. The myocardial collagen matrix consists of a network of fibrillar collagen which is intimately connected to the myocyte. Most collagen fibers reside in parallel with myocytes. These fibers may have a wavy, taut or coiled appearance. Fibrillar collagen types I and III are the major components of the myocardial collagen matrix. Collagen type I has been found to represent nearly 80% of the total collagen protein, while type III collagen is present in lower proportions (approximately 11%). Cardiac fibroblasts are the cellular source of fibrillar collagen, cardiac myocytes expressing only mRNA for type IV collagen. Collagens types I and III exhibit a high tensile strength which plays an important role in the behavior of the ventricle during the cardiac cycle. The collagen concentration and the intermolecular cross-linking of collagen increase with age. Measurements of collagen content in myocardial tissue suggest that it is the type I collagen fibers that increase in number and thickness in the aged. At the same time, electron microscopic observations have shown an increase in the number of collagen fibrils with a large diameter in the aging heart. The mechanism responsible for the myocardial fibrosis in the senescent myocardium is unclear. The collagen deposition in the myocardium could be due to the regulation of collagen biosynthesis at pre-translational levels. It is possible that the regulatory elements involved in this process are growth factors such as TGF-beta 1 and hormones and neurotransmitters. Details of regulatory mechanism that may come into play during aging may be elucidated by further investigations. The accumulation of collagen within the myocardium increases muscle stiffness. Myocardial function is affected by this process; this is usually reflected by incomplete relaxation during early diastolic filling, and presumably account for the decrease in early left ventricular diastolic compliance.

Collagen↗
PubMed1992

Incorporation of sodium fluoride into cortical bone does not impair the mechanical properties of the appendicular skeleton in rats.

Clinical studies on the use of sodium fluoride (NaF) in osteoporotic patients have demonstrated increased spinal bone mass without a reduction in vertebral fracture incidence, and a trend towards reduced appendicular bone mass with an increase in peripheral fracture incidence. As previous reports have suggested that NaF becomes incorporated into bone's crystal structure, possibly affecting bone strength, we sought to examine the relationship among bone fluoride content, bone mass, and skeletal fragility. Twenty-one-day-old female Sprague-Dawley rats were treated with four different doses of NaF. The tibiae were subjected to histomorphometric and biochemical analyses, and the femora were tested in torsion for the properties of strength, stiffness, energy storage capacity, and angular deformation. The results showed that over 50% of the skeleton in these rats was turned over in the presence of NaF. The four different doses resulted in a linear increase in bone F concentration and suggested excellent absorption and incorporation of this drug. No changes in histomorphometric indices of bone formation or turnover were found. Despite the large fraction of bone formed during NaF treatment, and the linear increase in bone fluoride content in relation to dose, there were no changes observed in any of the mechanical properties. These results suggest that, even extensive incorporation of fluoride into bone, in the absence of an effect on bone mass or remodeling, does not significantly alter its capacity to withstand mechanical loads.

Animals↗
PubMed2001

Direct measurements of multiple adhesive alignments and unbinding trajectories between cadherin extracellular domains.

Direct measurements of the interactions between antiparallel, oriented monolayers of the complete extracellular region of C-cadherin demonstrate that, rather than binding in a single unique orientation, the cadherins adhere in three distinct alignments. The strongest adhesion is observed when the opposing extracellular fragments are completely interdigitated. A second adhesive alignment forms when the interdigitated proteins separate by 70 +/- 10 A. A third complex forms at a bilayer separation commensurate with the approximate overlap of cadherin extracellular domains 1 and 2 (CEC1-2). The locations of the energy minima are independent of both the surface density of bound cadherin and the stiffness of the force transducer. Using surface element integration, we show that two flat surfaces that interact through an oscillatory potential will exhibit discrete minima at the same locations in the force profile measured between hemicylinders covered with identical materials. The measured interaction profiles, therefore, reflect the relative separations at which the antiparallel proteins adhere, and are unaffected by the curvature of the underlying substrate. The successive formation and rupture of multiple protein contacts during detachment can explain the observed sluggish unbinding of cadherin monolayers. Velocity-distance profiles, obtained by quantitative video analysis of the unbinding trajectory, exhibit three velocity regimes, the transitions between which coincide with the positions of the adhesive minima. These findings suggest that cadherins undergo multiple stage unbinding, which may function to impede adhesive failure under force.

Animals↗