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Biomedical subjects

J E Compston

Publications and source records attributed to J E Compston.

At least 55 records · Page 3Linked to original sources
PubMed1999

Immunolocalisation of vascular endothelial growth factor (VEGF) in human neonatal growth plate cartilage.

Angiogenesis is essential for the replacement of cartilage by bone during growth and repair. In order to obtain a better understanding of the mechanisms regulating vascular invasion at sites of endochondral ossification we have investigated the expression of the endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), by chondrocytes in human neonatal growth plates. VEGF was absent from chondrocytes in the resting zone and only weakly expressed by occasional chondrocytes in the proliferating region. In the hypertrophic zone the number of chondrocytes stained and the intensity of staining for VEGF increased with chondrocyte hypertrophy, maximum expression of VEGF being observed in chondrocytes in the lower hypertrophic and mineralised regions of the cartilage. These observations provide the first demonstration of the presence of VEGF in situ in developing human bone and are consistent with in vitro observations demonstrating the upregulation of proangiogenic growth factor production with increasing chondrocyte hypertrophy. The presence of numerous small blood vessels and vascular structures in the subchondral region where VEGF expression was maximal indicates that VEGF produced by hypertrophic chondrocytes may play a key role in the regulation of vascular invasion of the growth plate.

Cartilage↗
PubMed1999

Mechanism of bone loss after liver transplantation: A histomorphometric analysis.

Organ transplantation is associated with increased bone loss and high fracture risk, but the pathophysiological mechanisms responsible have not been established. We have performed a histomorphometric analysis of bone remodeling before and 3 months after liver transplantation in 21 patients (14 male, 7 female) aged 38-68 years with chronic liver disease. Eight-micrometer undecalcified sections of trans-iliac biopsies were assessed using image analysis. Preoperatively, bone turnover was low with a tendency toward reduced wall width and erosion depth. The bone formation rate increased from 0.021 +/- 0.016 (mean +/- SD) to 0.067 +/- 0.055 microm2/microm/day after transplantation (p < 0.0002) and activation frequency from 0.24 +/- 0.21/year-1 to 0.81 +/- 0. 67/year-1 (p < 0.0001). No significant change was observed in wall width, but there was a trend toward an increase in indices of resorption cavity size. There was a small increase in osteoid seam width postoperatively (p< 0.02) and decrease in mineralization lag time (p < 0.001). No significant changes in indices of cancellous bone structure were observed in the postoperative biopsies. These results demonstrate a highly significant and quantitatively large increase in bone turnover in the first 3 months after liver transplantation. Although no significant disruption of cancellous bone structure was demonstrated during the time course of the study, the observed changes in bone remodeling predispose to trabecular penetration and may thus result in long-term adverse effects on bone strength.

Adult↗
PubMed1999

Changes in calcium homoeostasis in patients undergoing liver transplantation: effects of a single infusion of pamidronate administered pre-operatively.

Bone turnover, bone loss and fracture risk increase after liver transplantation. It has been postulated that peri-operative administration of a bisphosphonate might prevent bone loss and reduce fracture rate. We studied the effects of a single pre-operative dose of pamidronate on biochemical parameters of skeletal metabolism in the first month after liver transplantation. In a randomized, single-blind study, six of 12 patients with chronic liver disease received 60 mg of pamidronate intravenously on a single occasion 1-30 days before transplantation. Six other patients undergoing transplantation received no pamidronate. We measured serum calcium, phosphate, albumin, bone-specific alkaline phosphatase, plasma parathyroid hormone and tartrate-resistant acid phosphatase before pamidronate infusion and at frequent intervals during the first 30 post-operative days. In treated patients, plasma parathyroid hormone increased 12-fold over baseline values and remained elevated in comparison with baseline at days 26-30; serum calcium and phosphate fell significantly, returning to normal at around day 14 post-operatively. There were no significant changes in any parameter in the untreated group. No changes in bone formation or resorption markers were observed in either group. The large increase in plasma parathyroid hormone concentrations in the treated group is probably secondary to the fall in serum calcium. The magnitude of the increase is much greater than that seen after pamidronate infusion in other patient groups. The lack of change in, or correlation of, serum calcium and plasma parathyroid hormone in the untreated group suggests that additional factors release calcium from bone after liver transplantation, presumably by increasing bone resorption.

Adult↗
PubMed1998

Effect of estrogen suppression on the mineralization density of iliac crest biopsies in young women as assessed by backscattered electron imaging.

The effects of estrogen suppression on bone mineralization in young women were studied by quantitative backscattered electron (BSE) imaging of transiliac biopsies taken before and after treatment for endometriosis. Treatment (6 months) was with analogs of gonadotrophin releasing hormone (GnRH) given either alone (six paired biopsies), which resulted in a marked reduction in the levels of circulating estrogen, or in conjunction with tibolone, a synthetic steroid with estrogenic, progestrogenic, and androgenic properties (four paired biopsies). Estrogen withdrawal increased (p < 0.01) and concomitant tibolone treatment decreased (p < 0.05) the overall mean bone density. Estrogen withdrawal increased the fraction of bone with a high mineralization density [pretreatment: 0.236+/-0.007; GnRH: 0.279+/-0.009, mean +/- standard error of the mean (SEM); p < 0.01]. The concomitant addition of tibolone reversed these effects and increased the proportion of bone with a low mineralization density (pretreatment: 0.198 +/- 0.005; tibolone: 0.230 +/-0.008, p < 0.01). Using previously published data, the mean bone density was inversely correlated with mean wall thickness in cancellous bone (p = 0.030) and with the percentage of active osteons (p = 0.023) in cortical bone. Although treatment had similar effects on the mean bone mineralization density of cortical and cancellous bone, there were different distributions of mineralization between the two sites, with cancellous bone having more skewed and kurtotic distributions both before and after estrogen withdrawal. This study indicates that a short-term estrogen suppression results in the accumulation of bone with a higher mineralization density. As bone with a high mineral content has a decreased impact resistance, this might increase fracture risk. Understanding the cellular and biochemical mechanisms responsible for the local distribution of bone mineral when estrogen is withdrawn may allow the development of new strategies for maintaining bone quality after menopause.

Adult↗
PubMed1998

Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development.

Stromelysin, a member of the matrix metalloproteinase family, demonstrates wide substrate specificity with the ability to degrade proteoglycan, fibronectin, laminin, casein, and the nonhelical region of collagen. The two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. However, the distribution of the two isoforms in bone has not been reported. We investigated the presence of SL-1 and SL-2 in human osteophytic and neonatal rib bone using immunohistochemistry and, combined with a new method of in situ zymography, determined the activity of the immunolocalized stromelysins. Latent SL-1 was strongly expressed in the extracellular matrix in fibrous tissue surrounding areas of endochondral ossification in osteophytes, and adjacent to the periosteum of fetal rib bone. Active SL-1 expression was detected in osteocytes and the matrix surrounding osteocytic lacunae. SL-2 showed intense cell-associated staining at sites of resorption in areas of endochondral ossification and in resorptive cells at the chondro-osseous junction, which correlated with enzyme activity detected by zymography. Within the rib, active SL-2 expression was localized in chondrocytes of the growth plate, whereas only occasional SL-1 signal was evident. Vascular areas showed strong SL-2 staining with some proteolytic activity. SL-2, but not SL-1, was strongly expressed in osteoclasts and most mononuclear cells within the marrow. At sites of bone formation both isoforms were expressed by osteoblasts with SL-1 also present in osteoid. These results demonstrate, for the first time, the differential expression of SL-1 and SL-2 in developing human bone, indicating specific roles for the two isoforms. In situ zymography demonstrates that SL-2 is produced in an active form with associated degradation, whereas SL-1, in a matrix-bound proenzyme form, may act as a reservoir for later activation.

Glycoproteins↗
PubMed1998

Expression and distribution of transforming growth factor-beta isoforms and their signaling receptors in growing human bone.

Transforming growth factors type beta (TGF-beta1, -beta2, and -beta3) are potent stimulators of bone formation and have been shown to regulate chondrocyte, osteoblast, and osteoclast formation and function. However, the distribution of the different isoforms and their signaling receptors in human bone in vivo has not previously been reported. Using samples of normal (neonatal rib) and pathological (osteophytic) developing human bone, we have investigated the expression of the different TGF-beta isoforms and their signaling receptors (TGF-betaRI and RII) at the messenger ribonucleic acid (mRNA) and protein levels by in situ hybridization and immunolocalization to establish the sites of TGF-beta production and their possible sites of action during human bone development in vivo. All three TGF-beta isoforms and the receptors were detected at sites of endochondral and intramembranous ossification. At sites of endochondral ossification, TGF-beta2 was detected in all zones of the cartilage, with the highest expression seen in the hypertrophic and mineralizing zones. TGF-beta3 was detected in proliferative and hypertrophic zone chondrocytes, while TGF-beta1 expression was restricted to the proliferative and upper hypertrophic zones. TGF-betaRI and RII exhibited similar distributions with maximum expression in the hypertrophic and mineralizing zones in the neonatal rib but in the resting/proliferative zone in the developing osteophyte. At sites of intramembranous ossification TGF-beta3 was the most widely distributed isoform and showed both matrix- and cell-associated staining. TGF-beta2 and -beta1 were expressed almost exclusively at sites of mineralization. These observations demonstrate that the different TGF-beta isoforms and their receptors exhibit distinct but overlapping patterns of expression, and support the hypothesis that they are involved in the regulation of endochondral and intramembranous ossification during human bone development in vivo.

Activin Receptors, Type I↗
PubMed1998

Selective oestrogen receptor modulators: a new paradigm for HRT.

Selective oestrogen receptor modulators are a range of compounds which mimic some, but not all, agonist actions of oestrogen in different tissues. They were developed with the aim of maximizing the benefits of oestrogen-like drugs in a number of important conditions whilst reducing adverse side-effects. The molecular biology of oestrogen receptor signalling is discussed in relation to the pharmacological effects of this class of drugs. The results of clinical trial data with one member of this group (raloxifene) are documented and future developments outlined.

Breast Neoplasms↗
PubMed1997

Hormone replacement therapy.

Oestrogen deficiency at the menopause leads to bone loss primarily as a result of increased bone turnover and an increase in the activity of osteoclasts. Hormone replacement therapy (HRT) reverses these changes, preventing menopausal bone loss and reducing fracture risk at the spine, hip, and wrist, although the magnitude of this reduction has not been accurately established. The optimal duration of therapy for the prevention of osteoporosis is uncertain but there is increasing evidence that life-long treatment after the menopause may be required to maintain maximum protection against fracture. The extraskeletal effects of long-term oestrogen therapy include protection against cardiovascular disease and a possible increase in the risk of breast cancer; the persistence of these effects after therapy is withdrawn is uncertain although there is some evidence that the increase in risk of breast cancer is seen only in current users. Furthermore, there is increasing evidence that the use of progestogens in combined formulations does not substantially alter either the cardiovascular benefits or the increased risk of breast cancer, although further studies are needed in this area. The emergence of 'no-bleed' preparations in recent years has increased the acceptability of HRT for some women, particularly those in older age groups. Finally, the development of tissue-selective oestrogen agonists is an exciting advance which may enable life-long therapy after the menopause to protect against cardiovascular and bone disease in the absence of significant side-effects.

Aged↗
PubMed1997

The expression of thyroid hormone receptors in human bone.

The mechanism of action of thyroid hormones on bone is poorly understood. Thyroid hormones may act on bone cells either indirectly by increasing secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), or directly by influencing target genes via specific nuclear receptors. The presence of thyroid hormone receptors (TRs) has been demonstrated in human and rodent osteoblast-like cells and cell lines and recently in osteoclasts derived from an osteoclastoma in vitro. However, their presence in human bone in situ has not been reported. We have used specific polyclonal antibodies to TR-alpha 1, -alpha 2, and -beta 1 to investigate the expression of these receptors in sections of human osteophytes and heterotopic bone. Osteoblasts and osteoclasts were identified by alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), respectively, whereas chondrocytes were identified morphologically. At sites of endochondral and intramembranous bone formation, TR-beta 1 and the splice variant -alpha 2 were widely expressed by proliferating, mature, and hypertrophic chondrocytes and also in cells within the fibrous tissue and at the bone forming surfaces, respectively. They were also detected in osteoblasts, osteoclasts, and a few osteocytes at sites of bone remodeling. In contrast, TR-alpha 1 was the least expressed and was present mainly in osteoblasts at remodeling sites and in a few mature and undifferentiated chondrocytes. Our results show, for the first time, the presence and distribution of TRs in human bone in situ and suggest that the skeletal actions of thyroid hormones may be mediated via these receptors. Further studies are required to define the role of the individual receptor isoforms in bone metabolism.

Acid Phosphatase↗
PubMed1997

Distribution of matrix metalloproteinases and their inhibitor, TIMP-1, in developing human osteophytic bone.

Connective tissues synthesise and secrete a family of matrix metalloproteinases (MMPs) which are capable of degrading most components of the extracellular matrix. Animal studies suggest that the MMPs play a role in bone turnover. Using specific polyclonal antisera, immunohistochemistry was used to determine the patterns of synthesis and distribution of collagenase (MMP-1), stromelysin (MMP-3), gelatinase A (MMP-2) and gelatinase B (MMP-9) and of the tissue inhibitor of metalloproteinases-1 (TIMP-1) within developing human osteophytic bone. The different MMPs and TIMP showed distinct patterns of localisation. Collagenase expression was seen at sites of vascular invasion, in osteoblasts synthesising new matrix and in some osteoclasts at sites of resorption. Chondrocytes demonstrated variable levels of collagenase and stromelysin expression throughout the proliferative and hypertrophic regions, stromelysin showing both cell-associated and strong matrix staining. Intense gelatinase B expression was observed at sites of bone resorption in osteoclasts and mononuclear cells. Gelatinase A was only weakly expressed in the fibrocartilage adjacent to areas of endochondral ossification. There was widespread but variable expression of TIMP-1 throughout the fibrous tissue, cartilage and bone. These results indicate that MMPs play a role in the development of human bone from cartilage and fibrous tissue and are likely to have multiple functions.

Bone and Bones↗
PubMed1997

Detection of osteoporosis in patients with inflammatory bowel disease.

The risk of osteoporosis is increased in patients with inflammatory bowel disease: particularly in those with additional strong risk factors such as glucocorticoid therapy, hypogonadism, past history of fragility fracture or malnutrition. Where possible, bone densitometry should be performed to identify those in need of treatment, to avoid unnecessary treatment if bone density is normal and to monitor the effects of treatment designed to prevent bone loss. If bone densitometry is not available, treatment should be advised on the basis of strong risk factors. Hormone replacement therapy should be given to patients with hypogonadism and bisphosphonate therapy to those receiving long-term glucocorticoid treatment. The dose of glucocorticoids should be kept to a minimum and, where present, vitamin D deficiency should be corrected.

Bone Density↗