Biomedical subjects

J P Mansell

Publications and source records attributed to J P Mansell.

10 recordsLinked to original sources

PubMed2000

Temporal changes in collagen composition and metabolism during rodent palatogenesis.

Cleft lip and palate is a common craniofacial malformation in man. The aetiology is multifactorial and not known. Since collagen is a major structural component of the developing palate, we studied its composition and metabolism during palate shelf formation and elevation in the rat. Palatal shelves were harvested at embryonic days (E) 15, 16 and 17 as well as post-partum. Palatal collagen increased threefold from E15 to E17 and tenfold from E17 to 5-day-old pups. Palatal calcification was seen in the main, post-partum. Collagen cross-linking, which may be important in shelf elevation and union, varied. The concentration of hydroxylysyl-pyridinolone cross-links was greatest prior to shelf elevation, declining thereafter. Similarly, the highest concentration of dihydroxylysinononorleucine was seen at E16 and this supports the concept of a compliant mesenchymal shelf responding to an intrinsic elevating force. We then determined if enzymes responsible for matrix degradation, matrix metalloproteinases (MMP) and the tissue inhibitors of metalloproteinases (TIMPs) altered over the same time periods. MMP-2, and TIMP-1 and TIMP-2 were identified by gelatin zymography and reverse zymography, respectively. MMP-3 activity was determined with a fluorogenic substrate assay. TIMP-1, TIMP-2 and MMP-3 levels remained constant from E15 to E17. The MMP-2 levels showed a significant elevation from E15 to E16 and E16 to E17. This suggests the regulation of extracellular matrix is likely to be of importance in palate morphogenesis.

Animals↗

PubMed2000

Matrix turnover.

This review concentrates on how the major component of extracellular matrix, collagen, is catabolized. This process is important in a number of aspects of orthodontics since matrix is constantly turning over, the rate of which differs in embryogenesis, ageing, disease, and physiological processes, such as orthodontic tooth movement. It is not the purpose of this review to consider each process in detail. The aim is to give a clear account of the matrix metalloproteinases (a major family of proteinases) including their classification, properties, and functions.

Collagen↗

PubMed2000

Palatogenesis and potential mechanisms for clefting.

This review concentrates on mechanisms of palatogenesis. This includes theories of shelf elevation, the role of matrix and identification of molecules and growth factors, which have key roles. The areas where failure to develop could potentially lead to clefting are highlighted. A key part of shelf fusion is the breakdown of the medial edge epithelium, a process that is probably dependent on enzymes involved in matrix turnover. There is good evidence that the matrix metalloproteinases may provide a common link to the multiple genetic and environmental factors that are known to cause clefting.

Cleft Palate↗

PubMed1999

Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength.

The metabolism of bone collagen has received little attention in relation to age-related loss of bone mass and strength. The aim of the present study was to analyze bone collagen content and metabolism in human bone with respect to age. The material consisted of iliac crest bone biopsies from 94 individuals: 46 women (ages 18-96, mean age 60.8 years) and 48 men (ages 23-92, mean age 59.5 years). Excluded from the study were all individuals with known osteoporotic lumbar vertebral fractures and renal, hepatic, or malignant diseases. Prior to collagen analysis the biopsies were scanned in a pQCT scanner for density assessment and then tested biomechanically. The results showed a decline in apparent bone density with age (P < 0.0001), a decline in maximum stress, Young's modulus, and energy absorption with age (P < 0.001). Concomittantly, there was an age-related decline in the intrinsic collagen content with age (P < 0.001). However, there were no biochemical modifications of the bone collagen during aging. There were no significant differences between women and men in the slopes of the regressions-curves. When multiple regression analyses were performed, only apparent bone density came out as a significant contributor in the correlation to biomechanical properties. Nevertheless, the decrease in bone collagen content with age might indicate an increase in the mineralization degree (probably due to decreased bone turnover) and thereby a change in material properties of bone. In conclusion, the present study has shown that loss of bone mass plays the major role in loss of bone strength. However, there is also a change in bone composition during normal aging, leading to a decrease in collagen content and an increase in the degree of mineralization. At this skeletal site, in a normal population there was no change in the biochemical properties of bone collagen.

Adolescent↗

PubMed1999

Changes in collagen turnover in early acute respiratory distress syndrome.

Pulmonary fibrosis is a well-recognized feature of acute respiratory distress syndrome (ARDS). Using immunoassays of bronchoalveolar lavage (BAL), fluid we investigated the synthesis of type I procollagen (PICP) and type I/II collagen degradation products (COL2-3/4C(short) neoepitope) in patients with ARDS, acute lung injury (ALI), subjects with risk factors for ARDS (At Risk), and healthy/ventilated control subjects. PICP was measured by ELISA as a marker of type I procollagen synthesis. COL2-3/4C(short) neoepitope was measured by an inhibition ELISA as a marker of collagenase degradation of type I/II collagen. BAL was performed initially within 48 h of ventilation (Day 1) and then subsequently on Day 4. Dilution of epithelial lining fluid (ELF) was corrected for by plasma urea comparison. Increased PICP levels were observed in the ELF from ARDS and ALI subjects on Day 1 compared with subjects At Risk (median values, 124.9 and 95.0 ng/ml versus 38.0 ng/ml, respectively, p < 0.0005). By contrast, the levels of COL2-3/4C(short) neoepitope were significantly reduced in the subjects with ARDS versus the At Risk subjects (13.22 ng/ml versus 32.33 ng/ml, p < 0.0005). This translated into a greatly increased PICP:COL2-3/4C(short) ratio in the subjects with ARDS (p < 0.0001). There was a significant decline in the PICP level in the subjects with ARDS between Days 1 and 4 (n = 15, p < 0.05). Linear regression analysis showed a significant association between PICP and lung injury score in the subjects with ARDS (p = 0.01). Our data suggests an early shift in balance between type I collagen synthesis and degradation by collagenase. The resultant increase in type I collagen would favor matrix deposition and the development of pulmonary fibrosis in the lungs of subjects with ARDS.

Adolescent↗

PubMed1998

Abnormal cancellous bone collagen metabolism in osteoarthritis.

Biochemical investigations into the pathogenesis of osteoarthritis have, for the last two decades, concentrated on the mechanisms involved in the destruction of the articular cartilage. Although bone changes are known to occur, the biochemistry of the collagenous matrix within osteoarthritic bone has received scant attention. We report that bone collagen metabolism is increased within osteoarthritic femoral heads, with the greatest changes occurring within the subchondral zone. Collagen synthesis and its potential to mineralize were determined by the carboxy-terminal propeptide content and alkaline phosphatase activity, respectively. These data supported elevated new matrix formation. Our finding of a three- to fourfold increase in TGF-beta in osteoarthritic bone indicates that this might represent a stimulus for the increased collagen synthesis observed. Of additional significance is the hypomineralization of deposited collagen in the subchondral zone of osteoarthritic femoral heads, supporting a greater proportion of osteoid in the diseased tissue. The cross-linking of collagen was similar to that observed for controls. In addition, the degradative potential of osteoarthritic bone was considerably higher as demonstrated by increased matrix metalloproteinase 2 activity, and again the greater activity was associated with the subchondral bone tissue. The polarization exhibited in the metabolism of bone collagen from osteoarthritic hips might exacerbate the processes involved in joint deterioration by altering joint morphology. This in turn may alter the distribution of mechanical forces to the various tissues, to which bone is a sensitive responder. Bone collagen metabolism is clearly an important factor in the pathogenesis of osteoarthritis and certainly warrants further biochemical study.

Aged↗

PubMed1997

Expression of gelatinases within the trabecular bone compartment of ovariectomized and parathyroidectomized adult female rats.

Ovariectomized (ovx) and parathyroidectomized (ptx) rat models of disturbed bone metabolism have been widely used in evaluating bone changes resulting from hormonal depletion, and are characterized by elevated and depressed bone turnover, respectively. We report here the expression of gelatinases extracted from native trabecular bone in these models. Nine-month-old female Sprague-Dawley rats were sacrificed after 3 weeks following ovx or 10 days post ptx to determine the influence of these procedures on the levels of proximal tibial bone tissue gelatinases. Identification and quantitation of these enzymes were performed via gelatin gel zymography of native tissue extracts and laser densitometry of developed gels, respectively. In the ptx model, a reduction in tissue levels of pro- and active-MMP-2 and a 45 kDa activated fragment was seen, whereas ovx exhibited significant increases in these enzymes. The MMPs are therefore clearly under the influence of factors known to modulate bone remodeling in vivo. The study of MMP levels directly extracted from bone using these experimental models may assist in developing management regimes for metabolic bone diseases through the use of drugs aimed at controlling turnover.

Animals↗

PubMed1997

Biochemical evidence for altered subchondral bone collagen metabolism in osteoarthritis of the hip.

Osteoarthritis (OA) of the hip is invariably viewed as a disease primarily affecting the articular cartilage. Data presented in this report, however, demonstrate changes in the metabolic activity of the underlying trabecular bone tissue, the processes of which may represent a significant factor in the pathogenesis of hip OA. Trabecular bone tissue from OA subjects expressed significantly more matrix metalloproteinase (MMP)-2 (gelatinase A, 72 kDa type IV collagenase) when compared to age-matched osteoporotic (OP) and normal bone tissue. Alkaline phosphatase was also significantly elevated in OA bone tissue. The combination of increased MMP-2 and alkaline phosphatase indicates heightened collagen turnover in the subchondral bone compartment of osteoarthritic hips. The data obtained from this study warrant a closer investigation into the significance of these changes in OA and emphasize the multifactorial elements of the whole joint in the whole joint in the overall disease process.

Age Factors↗

PubMed1997

Do subchondral bone changes exacerbate or precede articular cartilage destruction in osteoarthritis of the elderly?

Research into the aetiology of osteoarthritis has for several decades been concentrated on the destruction of the articular cartilage, the initiating events being believed to be changes in the proteoglycans and subsequently in the supporting collagenous framework, whereafter the disease is irreversible. Recent evidence has supported an old contention that the underlying bone may be involved, namely, increased technetium scintigraphy correlated with increased severity of the osteoarthritis as demonstrated by joint narrowing, and a demonstration of increased metabolism of cancellous bone collagen compared to age-matched controls. These studies have not been able to answer the question of the primary initiating event: does increased bone metabolism initiate cartilage destruction or vice versa? However, recent detailed studies on animal models, particularly the macaque, have demonstrated that in this case thickening of the subchondral bone precedes fibrillation of the cartilage, which is possibly due to increased resistance of the bone to compression. Further, MRI studies on the guinea pig suggest that the initial site of activity is at the ligament bone insertion site, prior to endochondral bone sclerosis. We propose that the biomechanics of the joint are perturbed by the loss of tension from the ligament following trauma, leading to remodelling of the subchondral bone. Certainly in humans damage to the cruciate ligament often results in osteoarthritis. It may be that subclinical damage also ultimately results in osteoarthritis. Although the results from animal models will need to be treated with caution, the concept that bone ligament changes precede articular cartilage destruction should lead to a redirection of research, and perhaps therapy, for this important and cruelly disabling disease.

Aged↗

PubMed1994

Changes in collagen composition and cross-links in bone and skin of osteoporotic postmenopausal women treated with percutaneous estradiol implants.

OBJECTIVE: To determine the effects of percutaneous estradiol (E2) implants on the collagen composition and maturity in the bone and skin of osteoporotic postmenopausal women. METHODS: Sixteen postmenopausal women with low bone mineral density were treated for 1 year with 75-mg E2 implants. Iliac crest bone and skin biopsies were analyzed for collagen content and collagen cross-links before treatment and at 1 year. Dual energy x-ray absorptiometry of the lumbar spine and proximal femur was also performed before and after 1 year of therapy. RESULTS: The cortical bone showed a significant increase in the mature cross-links of both hydroxylysylpyridinoline (P < .01) and lysylpyridinoline (P < .01), with a significant reduction in the percentage of collagen (P < .001). The pattern was similar in trabecular bone, with lysylpyridinoline increasing significantly (P < .05). The skin exhibited a significant reduction in the immature cross-link hydroxylysinonorleucine (P < .01), but no significant change in the percentage of collagen content or the mature cross-link histidinohydroxylysinonorleucine. The median increases in bone density were 11.5% at the spine and 4.34% at the total hip. The median post-treatment serum E2 level was 639 pmol/L. CONCLUSIONS: Bone mineral density increased at all the sites measured in the spine and proximal hip. The quality of the collagen within the transiliac biopsies had matured in that the concentration of the mature collagen cross-links had increased. These findings support a reduction in the turnover of bone collagen following estrogen replacement therapy. More important, the formation of a more mature collagen fiber should help to reduce the risk of future bone fracture.

Absorptiometry, Photon↗