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Biomedical subjects

R S Mason

Publications and source records attributed to R S Mason.

At least 19 recordsLinked to original sources
PubMed2004

1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway.

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is anti-apoptotic in human keratinocytes, melanocytes and fibroblasts after ultraviolet (UV)-exposure. To date, there is no published data on the effects of 1,25(OH)(2)D(3) or its analogs on DNA damage in irradiated skin cells. In these skin cells, 24h pre-treatment with 1,25(OH)(2)D(3) dose-dependently (10(-12) to 10(-8)M) decreased CPD damage by up to 60%. This photoprotective effect was also seen if the 1,25(OH)(2)D(3) was added immediately after irradiation and was mimicked by QW-1624F2-2 (QW), a low-calcemic 1beta-hydroxymethyl-3-epi-16-ene-24,24-difluoro-26,27-bis homo hybrid analog. The well-studied low calcemic, rapid acting agonist analogs 1alpha,25(OH)(2)lumisterol(3) (JN) and 1alpha,25(OH)(2)-7-dehydrocholesterol (JM) also protected skin cells from UV-induced cell loss and CPD damage to an extent comparable with that of 1,25(OH)(2)D(3). In contrast, the rapid response antagonist analog 1beta,25(OH)(2)D(3) (HL) completely abolished the photoprotective effects (reduced cell loss and reduced CPD damage) produced by treatment with 1,25(OH)(2)D(3), JN, JM and QW. Evidence for involvement of the nitric oxide pathway in the protection from CPD damage by 1,25(OH)(2)D(3) was obtained. These data provide further evidence for a role of the vitamin D pathway in the intrinsic skin defenses against UV damage. The data also support the hypothesis that the photoprotective effects of 1,25(OH)(2)D(3) are mediated via the rapid response pathway(s).

Apoptosis↗
PubMed2003

Osteocyte viability with glucocorticoid treatment: relation to histomorphometry.

BACKGROUND: Glucocorticoid induced osteoporosis is a common clinical problem. OBJECTIVE: To determine the pathophysiology of glucocorticoid induced osteoarthritis at the organ level. METHODS: Iliac crest biopsy specimens were obtained from nine patients receiving prednisone treatment for rheumatoid arthritis. Osteocyte viability and histomorphometric indices were assessed. RESULTS: Compared with controls, glucocorticoid treated subjects had reduced trabecular thickness and increased erosion. The number of viable osteocytes was significantly decreased in glucocorticoid treated patients compared with controls. CONCLUSION: The impaired bone formation, increased erosion and, importantly, loss of viable osteocytes are all likely to contribute to the increased risk of fracture in these patients.

Aged↗
PubMed2002

Tyr-TGFalpha transgenic mice develop ocular melanocytic lesions.

Transforming growth factor-alpha (TGFalpha) has been implicated in melanocyte transformation, as it is expressed in melanocytic lesions and in melanoma cells. We investigated its role in melanoma development using a transgenic mouse model. The mice were generated by microinjection of a transgene with 270 bp of the mouse tyrosinase promoter and the cDNA for human TGFalpha. No significant skin abnormalities were found, but individuals from three transgenic lines developed ocular melanocytoses (seven out of 10 transgenics), usually after a long latency period. In particular, the melanocyte component of the choroid was thicker than in non-transgenic controls, consistent with hyperplasia. The retinal pigment epithelium was unaffected. Melanocytic lesions were also present in the posterior eye, and abnormal distributions of melanocytes were found in neural tissue of the brain, skeletal muscle of the head and the Harderian glands, indicating migration from the choroid. It was concluded that mice engineered to express the normal growth factor TGFalpha from a tyrosinase promoter spontaneously developed melanocytic lesions in the eye but not the skin.

Animals↗
PubMed2001

Osteoporosis influences the early period of fracture healing in a rat osteoporotic model.

Osteoporotic fractures commonly occur in the elderly. Although current therapies are aimed at the prevention and treatment of osteoporotic fractures, studies examing the fracture healing process in osteoporotic bone are limited. We produced an osteoporotic rat model by ovariectomy (ovx) and maintained a low calcium diet (LCD) in order to evaluate the influence of osteoporosis on fracture healing. Callus formation and strength was monitored over a 3 week period by histological and biomechanical assessment. Data collected simultaneously on a group of rats undergoing sham surgery (sx) were used for comparison. A 40% reduction in fracture callus cross-sectional area and a 23% reduction in bone mineral density in the healing femur of the ovx rats was observed on day 21 following fracture as compared with the sx group (p < 0.01). Biomechanical data from the healing femur of the ovx rats revealed a fivefold decrease in the energy required to break the fracture callus, a threefold decrease in peak failure load, a twofold decrease in stiffness and a threefold decrease in stress as compared with the sx group (p < 0.01, respectively). Histomorphological analysis revealed a delay in fracture callus healing with poor development of mature bone in the ovx rats. This study provides physical evidence of altered fracture healing in osteoporotic bone, which may have important implications in evaluating the effects of new treatments for osteoporosis on fracture healing.

Animals↗
PubMed2001

Phosphate wasting in oncogenic osteomalacia: PHEX is normal and the tumor-derived factor has unique properties.

Oncogenic osteomalacia (OOM) is characterized by renal phosphate wasting and abnormal metabolism of vitamin D, somewhat similar to the phenotype of X-linked hypophosphatemic rickets (HYP). DNA from OOM tumor cells was analyzed for mutations in the PHEX gene, which is mutated in HYP. Screening for mutations by single-strand conformation polymorphism analysis and subsequent sequencing of all the exons revealed no mutations. Conditioned media from long-term cultures of OOM tumor cells were used to further characterize the physical properties of the phosphate-regulating factor and its mechanism of action. Inhibition of OK 3B2 cell renal phosphate transport by conditioned media was dose-dependent and maximal after 20 h. This time course differed from that of parathyroid hormone (PTH). The bioactivity was stable to mild acid and alkali treatment and freeze drying and was retained in the aqueous phase following organic solvent extraction. The activity was not suppressed by heat or by treatment with trypsin but was suppressed by the protease papain and had an apparent molecular weight of < 5000. No change was detected in the expression of type II sodium/phosphate cotransporter (NaPi) mRNA in OK 3B2 cells in response to conditioned media, unlike the reduction seen in Hyp mice. In the presence of colchicine or cytochalasin D, the inhibitory response to conditioned media was reduced, similar to the effect of these agents on the response to PTH. Cycloheximide also suppressed the inhibitory response of conditioned media, but not the response to PTH. These studies indicate that mutations in the PHEX gene are unlikely to be responsible for OOM and suggest that the tumor-derived factor that inhibits phosphate uptake is a small protein that does not downregulate type II NaPi mRNA, and requires an intact cytoskeleton and protein synthesis for activity.

Bone Neoplasms↗
PubMed2001

Regulation of epidermal growth factor receptor expression in human melanocytes.

The epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor alpha (TGFalpha), are reportedly involved in autocrine growth of melanoma cells. The signal pathway has also been implicated in early events of transformation, suggesting a function for EGFR in normal cells. This study reports the presence of EGFR in cultured melanocytes and examines some cellular responses to TGFalpha. Western analysis revealed 170 kDa bands in extracts of cultured neonatal human melanocytes, corresponding to the receptor Mr. Protein expression was more pronounced in cells during active growth. EGFR were less evident in cultures populated predominantly by melanized cells, indicating that receptor expression became reduced in differentiating cells. Immunocytochemistry confirmed these observations and also showed that EGFR reactivity was predominantly localized in the cell body but absent from dendrites. Addition of TGFalpha to early cultures induced a rapid increase in phosphotyrosine signal of the 170 kDa protein. Longer treatment (24-48 h) increased the intensity of the EGFR signal, suggesting that receptors had been upregulated. However, inclusion of TGFalpha in cultures did not result in an increase in cell numbers when compared to controls. The observations provide evidence of the existence of a receptor-mediated pathway in melanocytes which has transforming potential in vivo.

Cell Division↗
PubMed2001

Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets.

PHEX is the gene defective in X-linked hypophosphatemic rickets. In this study, analysis of PHEX revealed mutations in 22 hypophosphatemic rickets patients, including 16 of 28 patients in whom all 22 PHEX exons were studied. In 13 patients, in whom no PHEX mutation had been previously detected in 17 exons, the remaining 5 PHEX exons were analyzed and mutations found in 6 patients. Twenty different mutations were identified, including 16 mutations predicted to truncate PHEX and 4 missense mutations. Phenotype analysis was performed on 31 hypophosphatemic rickets patients with PHEX mutations, including the 22 patients identified in this study, 9 patients previously identified, and affected family members. No correlation was found between the severity of disease and the type or location of the mutation. However, among patients with a family history of hypophosphatemic rickets, there was a trend toward more severe skeletal disease in patients with truncating mutations. Family members in more recent generations had a milder phenotype. Postpubertal males had a more severe dental phenotype. In conclusion, although identifying mutations in PHEX may have limited prognostic value, genetic testing may be useful for the early identification and treatment of affected individuals. Furthermore, this study suggests that other genes and environmental factors affect the severity of hypophosphatemic rickets.

Adolescent↗
PubMed2001

Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging.

A previously healthy man with no family history of fractures presented with muscle pain, back pain and height loss. Investigations revealed hypophosphataemia, phosphaturia, undetectable serum 1,25-dihydroxyvitamin D and severe osteomalacia on bone biopsy, suggestive of a diagnosis of oncogenic osteomalacia. Thorough physical examination did not locate a tumour. Support for the diagnosis was obtained by detection of phosphate uptake inhibitory activity in a blinded sample of the patient's serum using a renal cell bioassay. On the basis of detection of this bioactivity, a total body magnetic resonance (MR) examination was performed. A small tumour was located in the right leg. Removal of the tumour resulted in the rapid reversal of symptoms and the abnormal biochemistry typical of oncogenic osteomalacia. Inhibitory activity was also demonstrated using the bioassay in serum from two other patients with confirmed or presumptive oncogenic osteomalacia, but not in serum from two patients with hypophosphataemia of other origin. This is the first case to be reported in which the diagnosis of oncogenic osteomalacia was assisted by demonstration of inhibitory activity of the patient's serum in a renal cell phosphate bioassay that provided an impetus for total body MR imaging.

Adult↗
PubMed2000

Nitric oxide regulates alkaline phosphatase activity in rat fracture callus explant cultures.

Nitric oxide (NO) is synthesised by a group of enzymes called nitric oxide synthases (NOS) and oxidizes to its stable end-products nitrite (NO2-) and nitrate (NO3-) We have previously reported in an in vivo rat model that NO is an important regulator for rat bone fracture healing. This study examines the effects of NO on alkaline phosphatase (ALP) activity in a rat fracture callus explant culture system. Explants of rat femoral fracture callus from days 4, 7, 14 and 28 post fracture induced NO2 release and ALP activity in a biphasic temporal manner, with the highest activity on day 7 and the lowest activity on day 14. Inhibition of NOS by co-incubation with an NOS inhibitor, S-(2-aminoethyl) isothiouronium bromide hydrobromide (AETU), inhibited ALP activity by an average of 50% at each time point (P <0.01). Supplementation with NO donor 3-morpholinosydnonomine hydrochloride (SIN-1) at low doses (25 and 0.025 microM) increased ALP activity by 20% (P < 0.01). ALP mRNA and histochemical ALP activity were localised to osteoblast-like and chondrocyte-like cells within fracture callus. The current study provides evidence that NO plays a regulatory role in ALP activity during rat fracture healing.

Alkaline Phosphatase↗
PubMed2000

Differential potency of beclomethasone esters in-vitro on human T-lymphocyte cytokine production and osteoblast activity.

Beclomethasone dipropionate is an inhaled corticosteroid, used for the treatment of asthma. It is metabolised to 17-beclomethasone monopropionate, which has greater affinity for corticosteroid receptors than the parent compound, and to beclomethasone. We investigated the potency of beclomethasone dipropionate, 17-beclomethasone monopropionate and beclomethasone (compared with dexamethasone as a reference steroid) in two different human cell types, peripheral blood mononuclear cells and osteoblasts. We found that beclomethasone dipropionate, 17-beclomethasone monopropionate (EC50 10(-14) M) and beclomethasone (EC50 approx. 10(-12) M) were much more potent than dexamethasone (EC50 10(-8) M) in inhibiting interleukin-5 production by peripheral blood mononuclear cells. In contrast, beclomethasone dipropionate, 17-beclomethasone monopropionate and beclomethasone were equipotent with dexamethasone (EC50 range 0.3-1.2 x 10(-9) M) in affecting several functional assays of osteoblasts (e.g. alkaline phosphatase activity and osteocalcin synthesis). These results show that the relative bioactivities of corticosteroids vary between different human cell types, and that affinities observed in receptor binding assays are not necessarily predictive of the bioactivity in cell populations, such as peripheral blood mononuclear cells and osteoblasts, which are putatively relevant to efficacy and side effects respectively.

Administration, Topical↗
PubMed1999

Elevated expression of FGF-2 does not cause prostate cancer progression in LNCaP cells.

BACKGROUND: Androgen-independent (AI) prostate cancer (CaP) resulting from progression of disease is untreatable. Such progression may relate to upregulation and autocrinicity of growth factor expression. We studied one candidate growth factor, basic fibroblast growth factor (FGF-2). METHODS: LNCaP cells made autocrine for FGF-2 by stable transfection with FGF-2 were examined for cancer progression, measured by 1) altered response to androgen, 2) ability to grow more quickly when cocultured with bone cells in vitro or to form tumors when coinoculated with bone cells in vivo, or 3) increase in metastatic ability. RESULTS: Stably transfected lines differed in FGF-2 protein expression. LNCaP-HF (high production of FGF-2) expressed more FGF-2 than LNCaP-LF (low production of FGF-2); controls were negative. In vitro, compared with LNCaPs, LNCaP-HF cells showed a slightly increased growth rate, reduced proliferation in response to androgen but not to estrogen or progesterone, and a decreased proliferative response to epidermal growth factor (EGF) and FGF-2. Although giving a slightly faster take rate, LNCaP-HF cells without Matrigel only formed small, fast-regressing tumors in male nude mice, and with Matrigel, did not differ from LNCaPs in growth rate or tumor size. No metastases occurred. No tumors grew in females. Mixed growth of FGF-2 transfectants with human fetal osteoblasts failed to cross-stimulate in vitro, or to allow tumor formation in vivo. CONCLUSIONS: Although FGF-2 is overexpressed in AI CaPs, our experiments show that upregulation of FGF-2 expression is not sufficient to cause androgen independence, tumorigenicity, or metastases production (i.e., prostate cancer progression) in LNCaP cells.

Animals↗
PubMed1999

Topical all-trans retinoic acid augments ultraviolet radiation-induced increases in activated melanocyte numbers in mice.

We have previously shown that daily application of 0.05% retinoic acid to the backs of lightly pigmented, hairless HRA:Skh-2 mice increases melanogenesis resulting from exposure to solar-simulated ultraviolet radiation. In this study we show that as early as 1 wk following commencement of treatment, there is a 2- fold increase in the number of epidermal 3,4-dihydroxyphenylalanine positive melanocytes in retinoic acid and ultraviolet radiation treated HRA:Skh-2 mice compared with mice that received ultraviolet radiation only. This increased to a 2.9-fold difference by 6 wk. Retinoic acid also augmented ultraviolet radiation-stimulated melanogenesis, with a 4-fold increase being observed after only 2 wk. These findings were also seen in C57BL mice. Ultraviolet radiation and retinoic acid needed to be applied to the same skin site for the augmentation in melanocyte activation to occur. Ultraviolet B rather than ultraviolet A was mainly responsible for melanogenesis and the retinoic acid primarily increased ultraviolet B-induced melanogenesis. Furthermore, retinoic acid on it's own, in the absence of ultraviolet radiation caused a small but statistically significant increase in 3,4-dihydroxyphenylalanine positive melanocyte numbers and melanogenesis. Thus topical retinoic acid is a potent modulator of melanocyte activation. Alone it is able to increase the number of activated epidermal melanocytes and make melanocytes more sensitive to activation by ultraviolet B.

Animals↗
PubMed1998

Tumor expression studies indicate that HEM-1 is unlikely to be the active factor in oncogenic osteomalacia.

HEM-1 was isolated as a putative factor responsible for oncogenic osteomalacia by Kumar et al. (Proc Assoc Am Phys 107:296-305; 1995). The cDNA was identified on the basis of PTH-like immunoreactivity; however, no studies have been reported of the expression of HEM-1 mRNA in oncogenic osteomalacia tumors. In this study, expression of HEM-1 mRNA was investigated in two oncogenic osteomalacia tumors and in a series of normal tissues. An HEM-1 PCR product was amplified from a cDNA library from one of the tumors, with six base changes identified, as compared with the published sequence. No expression was detected, however, in the oncogenic osteomalacia tumors either by Northern blot analysis or by reverse transcriptase PCR. This indicates that, although a region of HEM-1 sequence is present in the tumor cell cDNA library, any HEM-1 expression must be at very low levels. It is unlikely, therefore, that the HEM-1 product is the active factor responsible for oncogenic osteomalacia. In the normal tissues examined, human placenta, fibroblasts, parathyroid gland, liver, fetal bone, and rat kidney cortex, HEM-1 mRNA was not detected, suggesting that it does not have a physiological role in these tissues.

Adenocarcinoma↗
PubMed1998

Comparative effects of anti-inflammatory corticosteroids in human bone-derived osteoblast-like cells.

While effects of inhaled corticosteroids on serum markers of bone metabolism in normal and asthmatic subjects have been reported, there are little data on the direct effects of these corticosteroids on end-organs such as bone. The results presented here compare the effects of budesonide and its epimers (22S- and 22R-budesonide), fluticasone and dexamethasone on growth and differentiation of cultured human bone cells. Osteoblast-like cells were cultured from human foetal bone chips grown to confluence and used at first subculture. At concentrations of 10(-11)-10(-7) M each corticosteroid (CS) caused a dose-dependent decrease in [3H]thymidine incorporation into deoxyribonucleic acid (DNA), median effective concentration (EC50): fluticasone (0.06 nM) >22R (0.26 nM) >22S (0.4 nM) >budesonide (0.47 nM) >dexamethasone (1.5 nM). Each CS resulted in a dose-dependent increase in alkaline phosphatase activity, EC50: fluticasone (0.14 nM) >22R (0.2 nM)=22S (0.2 nM) >budesonide (0.4 nM) >dexamethasone (1.6 nM). The 1,25 dihydroxyvitamin D3 (1,25(OH)2D3)-stimulated osteocalcin production was decreased in the presence of each CS, EC50: fluticasone (0.02 nM) >22S (0.1 nM) >22R (0.2 nM) >budesonide (1.0 nM) >dexamethasone (1.8 nM). In human bone cells the potencies of fluticasone and budesonide in relation to dexamethasone are not dissimilar to those derived from human lymphocytes in vitro.

Alkaline Phosphatase↗
PubMed1998

Modulation of skin cell functions by transforming growth factor-beta1 and ACTH after ultraviolet irradiation.

The adaptive responses in skin to ultraviolet (UV) radiation include increased cornification of keratinocytes and increased synthesis and distribution of melanin by melanocytes. The possible involvement of paracrine factors in the generation of these responses was studied in a novel two-stage culture model. Human melanocytes or keratinocytes were first irradiated or sham-irradiated and then the conditioned media collected from these cells after 24 h were used to treat unirradiated skin cells. Immunofluorescent staining for transforming growth factor (TGF)-beta1 was increased in UV-irradiated keratinocytes compared with sham-irradiated cells. Increased TGF-beta1 was also detected in the culture media of irradiated keratinocytes. Treatment of unirradiated keratinocytes with conditioned media collected from UV-irradiated keratinocytes resulted in increased absolute numbers and percentages of cornified envelopes per well compared with treatment with conditioned media from sham-irradiated keratinocytes. The magnitude of this effect increased with increased dose of initial irradiation. The effects of conditioned media from UVR-treated cells were mimicked by authentic TGF-beta1. Treatment of conditioned media from irradiated cells with an antibody shown to neutralise the effects of TGF-beta1 but not with a non-immune antibody of similar isotype, abolished this bioactivity of the conditioned media from UV-irradiated cells. Immunofluorescent staining for ACTH was also increased in UV-irradiated keratinocytes. Conditioned media from UV-irradiated keratinocytes increased tyrosinase activity of unirradiated melanocytes, an effect which was mimicked by authentic ACTH. This bioactivity of conditioned media from irradiated keratinocytes was abolished in the presence of an antibody which neutralised the activity of ACTH but not MSH. These results provide evidence to support the involvement of TGF-beta1 and ACTH in the cornification and pigmentary responses respectively of skin cells after UV exposure.

Adrenocorticotropic Hormone↗
PubMed1997

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Oncogenic osteomalacia is a syndrome associated with rare, usually mesenchymal tumours, which is characterized by hypophosphataemia, phosphaturia and low concentrations of 1,25-dihydroxyvitamin D. The reversal of clinical and biochemical abnormalities following removal of the tumour, indicates it is the source of a humoral factor that is responsible for these abnormalities. It has been demonstrated that the humoral factor inhibits renal phosphate uptake and reduces 1,25-dihydroxyvitamin D production. Although there is evidence that it may act via parathyroid hormone/parathyroid hormone-related peptide receptors and may be a peptide, the factor has not yet been identified, nor has its relationship to factors involved in X-linked hypophosphataemic rickets been established. We propose unifying hypotheses for the pathogenesis of oncogenic osteomalacia and X-linked hypophosphataemic rickets which involve defects in the PEX gene. These hypotheses do not fully explain all the available data and it remains possible that hormone(s) with little or no role in X-linked hypophosphataemic rickets may be responsible for oncogenic osteomalacia.

Animals↗