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P Garnero

Publications and source records attributed to P Garnero.

At least 55 records · Page 3Linked to original sources
PubMed2001

Potential contribution of IL-17-producing Th(1)cells to defective repair activity in joint inflammation: partial correction with Th(2)-promoting conditions.

To assess the contribution of cell interactions to the production of cytokines and type I collagen, fixed synovium T cell clones were cocultured on synoviocytes and levels of IL-6, LIF and PICP, a marker of type I collagen synthesis measured. Levels of IL-6 and LIF were higher with Th(1)than with Th(0)and Th(2)clones. Levels of PICP were decreased with Th(1)clones and increased with Th(2)clones. IL-17-producing T cells, all Th(1), were among the highest inducers of cytokine and inhibitors of collagen synthesis. Preincubation of clones in Th(1)conditions (IL-12 plus anti-IL-4) increased IL-6 production, whereas Th(2)conditions (IL-4 plus anti-IL-12) strongly inhibited IL-6 production and restored repair activity. As rheumatoid synovium is infiltrated by Th(1)cells, local cell interactions result in a pro-inflammatory pattern with defective repair, which can be reversed at least in part, by a Th(2)pattern.

Arthritis, Rheumatoid↗
PubMed2001

A functional polymorphic variant in the interleukin-6 gene promoter associated with low bone resorption in postmenopausal women.

OBJECTIVE: To examine functional interleukin-6 (IL-6) -174 G-->C allelic variants in relation to bone turnover and bone mineral density (BMD) in postmenopausal women. METHODS: Four hundred thirty-four healthy women living in the community (mean +/- SD age 71.7 +/- 5.7 years) were genotyped for the IL-6 -174 G-->C polymorphism. Serum levels of C-telopeptide of type I collagen (CTx), a marker of bone resorption, and osteocalcin (OC), a marker of bone formation, were determined. BMD at the hip and forearm was measured by dual-energy x-ray absorptiometry. RESULTS: CTx levels differed significantly (P = 0.006) among IL-6 genotypes (mean +/- SEM 0.275 +/- 0.02 ng/ml, 0.325 +/- 0.01 ng/ml, and 0.356 +/- 0.02 ng/ml in women with the CC genotype [n = 68], the GC genotype [n = 204], and the GG genotype [n = 162], respectively). Compared with the GG group, age-adjusted odds ratios for high bone resorption were 0.65 (95% confidence interval [95% CI] 0.41-1.0, P = 0.06) and 0.37 (95% CI 0.18-0.73, P = 0.0047) in GC and CC subjects, respectively. In contrast, OC levels did not differ by genotype. BMD at the hip and forearm was 1.5-5% higher in CC subjects compared with GG subjects (P not significant). When the cohort was divided according to the median age (70.5 years), BMD was significantly decreased in older compared with younger postmenopausal women with the GG and GC genotypes (-9.6% on average; P < 0.01), but not in those with the CC genotype (-5.1% on average; P not significant). CONCLUSION: Compared with the GC and GG IL-6 -174 G-->C genotypes, the CC genotype is associated with lower bone resorption and lesser decrease in bone mass in older postmenopausal women. These results suggest that IL-6 -174 G-->C alleles may be significant determinants of the risk for osteoporosis in elderly subjects.

Aged↗
PubMed2001

The bisphosphonate zoledronate decreases type II collagen breakdown in patients with Paget's disease of bone.

Bisphosphonates have been suggested to be partially chondroprotective in animal models of arthritis. The aim of this study was to assess the short-term effect of the bisphosphonate zoledronate on type II collagen degradation in patients with Paget's disease of bone. Twenty-six patients with active Paget's disease who were a part of a double-blind, placebo-controlled, randomized study comparing the effects of several doses of a single injection of zoledronate, a potent bisphosphonate, were studied. Type II collagen destruction was assessed by urinary levels of type II collagen C-telopeptide (CTX-II) using a new immunoassay. Bone resorption was assessed by measuring the urinary excretion of nonisomerized type I collagen C-telopeptide (alpha CTX-I). Biochemical markers were measured at baseline and 5, 10, 30, and 60 days after injection. At baseline, no significant increase of CTX-II was observed in patients with Paget's disease compared with a group of 27 gender-and age-matched controls, in contrast to the ninefold (p < 0.0001) increase of urinary alpha CTX-I. After a single intravenous injection of zoledronate (200 or 400 microg), urinary CTX-II transiently decreased by a median of 25% 5 days after the injection of zoledronate (p = 0.0023 vs. placebo), then increased to pretreatment levels after 10 days. In contrast, urinary alpha CTX-I decreased within 5 days with a maximal decrease of 51% at day 10 (p < 0.001 vs. baseline and placebo), and levels remained suppressed during the 2 months of the study. Zoledronate not only reduces bone turnover but also directly decreases type II collagen degradation in patients with Paget's disease, suggesting that bisphosphonates may have chondroprotective effects in humans. Measurement of type II collagen breakdown by a new urinary biochemical marker may be useful for in vivo assessment of the effects of drugs that potentially inhibit cartilage destruction.

Aged↗
PubMed2001

Collagen type II C-telopeptide fragments as an index of cartilage degradation.

We report the development of an assay for measurement of the urinary concentration of collagen type II C-telopeptide fragments. This assay was developed for providing a specific marker of joint metabolism. A monoclonal antibody, recognizing a linear six amino acid epitope from the middle region of the collagen type II C-telopeptide was used in a competitive enzyme-linked immunoassay (ELISA) format for measurement of urine samples. The technical performance and specificity of the assay was evaluated and a panel of samples from patients with rheumatoid arthritis (RA) (n = 27), osteoarthritis (OA) (n = 29), Paget's disease (n = 9), and healthy controls (n = 428) was measured in the assay. The ELISA was specific for the peptide EKGPDP derived from collagen type II C-telopeptide: it did not recognize peptides from the N-telopeptide of the molecule or from other collagen types. Collagen type II C-telopeptide fragments measured in the assay resisted seven freeze-thaw cycles and >20 h of storage at room temperature. RA and OA patients showed significant 2.33-fold (95% confidence interval [CI] 1.50-3.16) and 1.53-fold (CI 1.24-1.82) elevations in CartiLaps concentration, respectively. Paget's disease patients did not have elevated CartiLaps levels. RA patients with radiological evidence of cartilage damage had significantly higher (1.79-fold, CI 1.04-2.54) CartiLaps levels than RA patients without radiological evidence of cartilage destruction. The Cartilaps assay showed high technical precision and an ability to differentiate populations with an elevated joint metabolism from normal controls. This suggests that the assay may have clinical value in assisting in the diagnosis of joint diseases and in monitoring progression and therapy in RA and OA.

Animals↗
PubMed2001

Markers of bone turnover in prostate cancer.

Prostate cancer is the most common malignancy in elderly men and is often associated with bone metastases. Although bone metastases are osteosclerotic, histological and biochemical studies clearly indicate an increase of both bone formation and bone resorption, providing the rational for using bisphosphonate as a palliative treatment in these patients. The recent development of specific and sensitive biochemical markers, reflecting the overall rate of bone formation and bone resorption, has improved the non-invasive assessment of bone turnover abnormalities in patients with prostate cancer. The immunoassays for bone-specific alkaline phosphatase and type I collagen propeptides are currently the most sensitive markers to assess bone, formation. The best indices of bone resorption are the immunoassay for the pyridinoline cross-links and the related peptides that can be measured in urine and more recently in serum. A better knowledge of the biochemistry, especially of the age-related post-translational modifications of type I collagen in the abnormal bone matrix, associated with bone metastases from prostate cancer may lead to markers of increased sensitivity. A recent example is the demonstration that the isomerization and racemization of the aspartic acid residue in C-telopeptides of type I collagen is impaired in patients with prostate cancer and bone metastases, a pattern than can be detected with specific conformational antibodies. The most sensitive markers of bone formation and bone resorption are markedly increased in patients with bone metastases compared with patients with cancer but without metastases, the levels correlating with the extent of the bone involvement. However, their sensitivity remains limited, suggesting that the currently available biochemical markers cannot be used as a surrogate for bone scintigraphy in the diagnosis of bone involvement. A few studies have suggested that the measurement of bone markers may be useful in the assessment of response to anti-endocrine therapy, although available data indicate a lower sensitivity than with prostates specific antigen. Additional longitudinal studies are required to assess the potential use of bone markers, especially to identify patients who relapse during the course of the treatment and, more specifically 3 those that result from the progression in bone metastases.Clearly, the established use of bone markers is for monitoring effects of bisphosphonate treatment. Several studies have shown a rapid decrease of bone resorption markers in patients with prostate cancer and bone metastases, the magnitude of the decrease correlating with the efficacy of the treatment in reducing bone pain. Thus, bone markers are likely to become a useful and objective tool to monitor bisphosphonate treatment and individual the therapy scheme.

Biomarkers↗
PubMed2001

Three-year follow-up of the use of transdermal 17beta-estradiol matrix patches for the prevention of bone loss in early postmenopausal women.

OBJECTIVE: A total of 325 of 569 postmenopausal women who were initially recruited into two 2-year, double-blind, placebo-controlled, dose-ranging studies of a matrix transdermal formulation of 17beta-estradiol (Menorest) participated in open-label extensions for a third year. STUDY DESIGN: Those patients originally randomly assigned to receive 17beta-estradiol continued active treatment with dosages of 25, 50, 75, or 100 microg/d, whereas those originally randomly assigned to receive a placebo patch were switched to an active patch of identical size that delivered 17beta-estradiol at 25, 50, 75, or 100 microg/d. Follow-up was conducted, and bone density and other parameters were compared. RESULTS: Overall, gains in bone mass were maintained in patients who received 3 years of active treatment. In patients originally randomly assigned to receive placebo, initial losses in bone mass during the first 2 years were reversed and replaced with marked increases after the switch to active treatment. All patients who had initially received placebo showed significant, dose-related, clinically relevant increases (2.77% +/- 0.99%; P =.0048; to 7.36% +/- 0.74%; P =.0001) in lumbar spine bone mineral density relative to the end of the second year of the original study; smaller final-year increases were noted among the patients who had been actively treated for all 3 years. Similar trends were reported for femoral, trochanter, and total hip bone mineral densities. Mean total body bone mineral density either increased or remained unchanged in all dosage groups. These results were accompanied by parallel changes in levels of serum and urinary markers of bone turnover, with all markers approaching or returning to premenopausal levels by month 36. The high tolerability of this formulation during years 1 and 2 was maintained during year 3; 5.5% of patients withdrew from treatment because of adverse events in the final year. CONCLUSION: The Menorest formulation of transdermal 17beta-estradiol maintained bone mineral density gains in postmenopausal women and was well tolerated through a 3-year treatment period. It was also effective in reversing the initial bone loss associated with late commencement of therapy.

Absorptiometry, Photon↗
PubMed2001

Urinary excretion of glucosyl-galactosyl pyridinoline: a specific biochemical marker of synovium degradation.

OBJECTIVE: Glucosyl-galactosyl pyridinoline (Glc-Gal-PYD), which has been identified in urine, is a glycosylated analogue of pyridinoline. The tissue distribution of this molecule has not been yet determined and its utility as a potential biochemical marker of joint degradation in patients with joint diseases has not been investigated. METHODS AND RESULTS: In this study, we demonstrate that Glc-Gal-PYD is abundant in human synovium tissue, absent from bone and present in minute amounts in cartilage and other soft tissues, such as muscle and liver. Using an ex vivo model of human joint tissue degradation, we found that Glc-Gal-PYD is released from synovium tissue, but not from bone and cartilage. The urinary level of Glc-Gal-PYD was increased by 109% in patients with rheumatoid arthritis (RA) compared with healthy adults, but was normal in patients with Paget's disease of bone. In addition, Glc-Gal-PYD was higher in those patients with destructive disease, as assessed by X-rays of the joints, than in those with non-destructive RA. CONCLUSION: Glc-Gal-PYD may be useful for the clinical investigation of patients with joint disease.

Adult↗
PubMed2001

Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage.

OBJECTIVE: To analyse the relations between the urinary levels of type II collagen C-telopeptide (CTX-II) and glucosyl-galactosyl pyridinoline (Glc-Gal-PYD)-two newly developed biochemical markers of type II collagen and synovial tissue destruction respectively-disease activity and the severity of joint destruction in patients with knee osteoarthritis (OA). The clinical performance of these two new markers was compared with that of a panel of other established biochemical markers of connective tissue metabolism. METHODS: The following biochemical markers were measured in a group of 67 patients with knee OA (mean age 64 years, median disease duration eight years ) and in 67 healthy controls: for bone, serum osteocalcin, serum and urinary C-telopeptide of type I collagen (CTX-I); for cartilage, urinary CTX-II, serum cartilage oligomeric matrix protein (COMP), and serum human cartilage glycoprotein 39 (YKL-40); for synovium, urinary Glc-Gal-PYD, serum type III collagen N-propeptide (PIIINP), serum hyaluronic acid (HA); and for inflammation, serum C reactive protein. Biochemical markers were correlated with pain and physical function (WOMAC index) and with quantitative radiographic evaluation of the joint space using the posteroanterior view of the knees flexed at 30 degrees. RESULTS: All bone turnover markers were decreased in patients with knee OA compared with controls (-36%, -38%, and -52%, p<0.0001 for serum osteocalcin, serum CTX-I and urinary CTX-I, respectively). Serum COMP (+16%, p=0.0004), urinary CTX-II (+25%, p=0.0009), urinary Glc-Gal-PYD (+18%, p=0.028), serum PIIINP (+33%, p<0.0001), and serum HA (+ 233%, p<0.0001) were increased. By univariate analyses, increased urinary Glc-Gal-PYD (r=0.41, p=0.002) and decreased serum osteocalcin (r=-0.30, p=0.025) were associated with a higher total WOMAC index. Increased urinary CTX-II (r=-0.40, p=0.0002) and Glc-Gal-PYD (r=-0.30, p=0.0046) and serum PIIINP (r=-0.29, p=0.0034) were the only markers which correlated with joint surface area. By multivariate analyses, urinary Glc-Gal-PYD and CTX-II were the most important predictors of the WOMAC index and joint damage, respectively. CONCLUSION: Knee OA appears to be characterised by a systemic decrease of bone turnover and increased cartilage and synovial tissue turnover. CTX-II, Glc-Gal-PYD, and PIIINP may be useful markers of disease severity in patients with knee OA.

Aged↗
PubMed2001

Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study.

During recent years, experimental data, case reports, and epidemiological studies have suggested an important role for estradiol in bone metabolism in men. In a cohort of 596 men, aged 51-85 yr, we measured bone mineral density (BMD) of the lumbar spine, hip, total body, and forearm; serum levels of sex steroid hormones [total and free testosterone, total estradiol (17betaE(2)), bioavailable estradiol (bio-17betaE(2)), androstenedione, and sex hormone-binding globulin]; and markers of bone turnover [serum osteocalcin, bone alkaline phosphatase, N-terminal extension propeptide of type I collagen, and beta-isomerized C-terminal telopeptide of collagen type I (betaCTX)], as well as urinary excretion of betaCTX and deoxypyridinoline (DPyr). An age-related decrease was found for bio-17betaE(2) (r = -0.16; P < 0.001), free testosterone (r = -0.25; P < 0.001), free testosterone index (r = -0.32; P < 0.001), and androstenedione (r = -0.22; P < 0.001), but not for total 17betaE(2) or total testosterone. 17betaE(2) and bio-17betaE(2), but not other hormones, were correlated with BMD after adjustment for age and body weight. In men with a bio-17betaE(2) level in the lowest quartile, the average BMD was lower than in men having a bio-17betaE(2) level in the highest quartile by 6.6-8.7% according to the site of measurement, which corresponded to 0.45-0.65 SD. In age- and body weight-adjusted models, bio-17betaE(2), but not other hormones, was negatively correlated with bone markers (e.g., osteocalcin: r = -0.14; P < 0.001; urinary betaCTX: r = -0.20; P = 0.0001; DPyr: r = -0.14; P < 0.001). In men with the lowest concentration of bio-17betaE(2) (first quartile), the concentrations of markers of bone turnover were higher by 11-35% (or 0.4-0.7 SD) than in men having the highest bio-17betaE(2) level (upper quartile). In men in the lowest quartile for bio-17betaE(2) and in the highest quartile for urinary DPyr or betaCTX, the BMD of total hip and that of distal forearm were 8% and 10% lower than in men in the highest quartile for bio-17betaE(2) and in the lowest quartile for DPyr or ssCTX. In the age- and body weight-adjusted multiple regression models, bio-17betaE(2) contributed significantly to the explanation for the variability in all markers. In summary, we found in a cross-sectional analysis of a cohort of men that low levels of bio-17betaE(2) are associated with high bone turnover and low BMD. These data suggest that the age-related decrease in bio-17betaE(2) contributes to bone loss in elderly men by increasing bone turnover. Low 17betaE(2) levels may be an important risk factor for osteoporosis in men.

Aging↗
PubMed2001

Effects of a new selective estrogen receptor modulator (MDL 103,323) on cancellous and cortical bone in ovariectomized ewes: a biochemical, histomorphometric, and densitometric study.

The aims of this study performed in ewes were: (1) to confirm in this animal model the effects on bone of ovariectomy (OVX) alone or associated with Lentaron (L), a potent peripheral aromatase inhibitor, used to amplify the effects of OVX and (2) to evaluate the effects of a new selective estrogen receptor modulator (SERM; MDL 103,323) on bone remodeling. Thirty-nine old ewes were divided into five groups: sham (n = 7); OVX (n = 8); OVX + L (n = 8); OVX + L + MDL; 0.1 mg/kg per day (n = 8); and OVX + L + MDL 1 mg/kg per day (n = 8). The animals were treated for 6 months. Biochemical markers of bone turnover (urinary excretion of type 1 collagen C-telopeptide [CTX], serum osteocalcin [OC], and bone alkaline phosphatase [BAP]) were measured each month. Bone biopsy specimens were taken at the beginning and after death at the end of the experiment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) on the lumbar spine and femur. OVX induced a significant increase in biochemical markers. This effect was the highest after 3 months for CTX (+156% vs. sham) and after 4 months for OC and BAP (+74% and +53% vs. sham, respectively). L tended to amplify the effect of OVX on OC and BAP. OVX induced significant increases in the porosity, eroded, and osteoid surfaces in cortical bone but no effect was observed in cancellous bone. MDL treatment reduced the bone turnover as assessed by bone markers, which returned to sham levels as well as histomorphometry both in cortical and in cancellous bone. Cancellous osteoid thickness decreased by 27% (p < 0.05), mineralizing perimeter by 81% (p < 0.05), and activation frequency by 84% (p < 0.02) versus OVX + L. Femoral and spinal BMD were increased by MDL and tended to return to the sham values. The effects of OVX on bone turnover were different on cortical and cancellous bone. These effects on cortical bone were reflected by changes in biochemical markers. MDL markedly reduces bone turnover and increases BMD suggesting that this new agent may prevent postmenopausal bone loss.

Alkaline Phosphatase↗
PubMed2001

Cross-sectional evaluation of bone metabolism in men.

There are relatively few data concerning age-related changes of bone turnover in men. The aim of the study was to evaluate age-related changes of the levels of serum and urinary biochemical markers of bone metabolism in a large cohort of 934 men aged 19-85 years and to investigate their association with bone mineral density (BMD). Bone formation was evaluated using serum levels of osteocalcin (OC), bone alkaline phosphatase (BAP), and N-terminal extension propeptide of type I collagen (PINP). Bone resorption was evaluated by measurement of urinary excretion of beta-isomerized C-terminal telopeptide of collagen type I beta-CTX) of free deoxypyridinoline (fDpyr) and total Dpyr (tDPyr) and of the serum level of beta-CTX. Levels of biochemical bone markers were very high in young men and decreased rapidly until the age of 40 years and then more slowly until 60 years of age. After the age of 60 years, markers of bone formation remained stable while resorption markers showed a moderate and variable increase with aging. Serum and urinary beta-CTX levels were elevated only in about 5% of elderly men. The age-related increase of urinary excretion of tDpyr and of its free and peptide-bound fractions was related to the presence of elevated levels in a subgroup of about 15% of elderly men. Before 60 years of age, levels of biochemical bone markers were not correlated with BMD, whereas after 60 years of age, they were correlated negatively with BMD. After adjustment for age and body weight, BMD in men with the highest levels of biochemical bone markers (i.e., in the upper quartile) was 1.8-12.5% (i.e., 0.25-0.89 SD) lower than in men with levels of biochemical bone markers in the lowest quartile. In conclusion, bone turnover in men is high in young adults and decreases to reach a nadir at 55-60 years of age. After the age of 60 years, bone resorption markers--but not bone formation markers--increase in some men and are associated with lower BMD, suggesting that this imbalance is responsible for increasing bone loss in elderly men.

Adult↗
PubMed2001

Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis.

BACKGROUND: Biochemical markers of bone turnover can provide prognostic information about the risk of osteoporotic fracture and are useful tools for monitoring efficacy of antiresorptive therapy. A serum-based automated assay may be of better clinical value than urinary markers because of lower imprecision and day-to-day within-person variability. Our aim was to evaluate the technical and clinical performances of a new, fully automated assay for serum C-terminal cross-linking telopeptide of type I collagen (CTX), a marker of bone resorption. METHODS: Serum CTX was measured on the Elecsys 2010 automated analyzer (Roche). Results were compared with those of the manual ELISA. We measured serum CTX concentrations in 728 healthy women, ages 31-89 years. We investigated the ability of this assay to predict the rate of postmenopausal forearm bone loss evaluated by four repeated bone mineral density measurements using dual-x-ray absorptiometry in 305 women followed prospectively for 4 years. Finally, in a cohort of healthy, untreated, postmenopausal women, we compared baseline serum CTX in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with values in the 380 women who did not fracture during a mean 5 years of follow-up. RESULTS: The within- (n = 21) and between-run (n = 21) CVs were <4.1% and 5.7%, respectively. In 728 healthy women, serum CTX concentrations (automated) correlated with those of the manual ELISA (r = 0.82; P<0.0001). The median long-term within-person variability assessed by four repeated measurements over 3 months in 18 postmenopausal women was 9.4%. Compared with 254 premenopausal women, serum CTX was 39% (P<0.0001) higher in 45 perimenopausal women and 86% (P<0.0001) higher in 429 postmenopausal women (mean age, 64 years). Baseline serum CTX correlated negatively with changes of bone mass measured at the mid (r = -0.23; P<0.0001) and distal (r = -0.27; P<0001) radius. Postmenopausal women with serum CTX greater than the mean + 2 SD values in premenopausal women accounted for 42% of the population, lost bone at the mid radius on average eightfold more rapidly than the other women (-0.27% +/- 2.92% vs. -2.25% +/- 3.95%; P<0.0001), and had increased risk of fracture with a relative risk (95% confidence interval) of 1.8 (1.01-3.1) after adjustment for physical activity. CONCLUSIONS: The automated assay for serum CTX is precise and predicts rate of bone loss and fracture risk in postmenopausal women. Because it is convenient to use and has high throughput, this serum bone resorption marker may be useful for the investigation of patients with osteoporosis.

Adult↗
PubMed2000

Racemization and isomerization of type I collagen C-telopeptides in human bone and soft tissues: assessment of tissue turnover.

Urinary excretion of the type I collagen C-telopeptide (CTx) has been shown to be a sensitive index of the rate of bone resorption. The human type I collagen sequence A(1209)HDGGR(1214) of CTx can undergo racemization of the aspartic acid residue Asp(1211) and isomerization of the bond between this residue and Gly(1212). These spontaneous non-enzymic chemical reactions takes place in vivo in bone, and the degree of racemization and isomerization of CTx molecules may be an index of the biological age and the remodelling of bone. The aim of the present study was to investigate the degree of racemization and isomerization of type I collagen in human connective soft tissues, in order to estimate the rate of collagen turnover in adult tissues and compare it with that of bone. We also performed a systematic evaluation of the pyridinium cross-link content in adult human tissues. Using antibodies raised against the different CTx forms, we found that bone and dermis are the tissues that show most racemization and isomerization. The type I collagen of arteries, lung, intestine, kidney, skeletal muscle and heart shows significantly less racemization and isomerization than that of bone, suggesting that these soft tissues have a faster turnover than bone. We also found that pyridinoline and, to a lesser degree, deoxypyridinoline are distributed throughout the different tissues investigated. Because bone type I collagen is characterized by a high degree of both racemization/isomerization and deoxypyridinoline cross-linking, the concomitant assessment of these two post-translational modifications is likely to result in a highly specific marker of bone resorption.

Aged↗
PubMed2000

Contribution of interleukin 17 to synovium matrix destruction in rheumatoid arthritis.

Interleukin (IL-)17 is a T cell-derived pro-inflammatory cytokine produced by RA synovium. We studied the role of IL-17 in the synovium cytokine network to determine whether it can influence the inflammatory and destructive pattern characteristic of RA. Herein, we investigated whether the production and action of MMP-1 and its inhibitor TIMP-1 could be modulated by IL-17 in the presence of pro-inflammatory cytokine (IL-1) and anti-inflammatory cytokines (IL-4, IL-13, IL-10). The effect of the blockade of endogenous IL-17 on the secretion of MMP-1 and TIMP-1 by RA synovium and matrix destruction was also studied. IL-17 increased the spontaneous production of MMP-1 by synoviocytes five-fold. IL-1 was more potent since it increased MMP-1 production nine-fold. Addition of IL-4, IL-13 and IL-10 to synoviocyte cultures reduced the spontaneous production of MMP-1 and induced TIMP-1 production by synoviocytes stimulated with IL-17 or/and IL-1beta. In the presence of anti-IL-17 blocking mAb, MMP-1 production and collagenase activity by RA synovium was reduced by 50% and associated with a 50% reduction in type I collagen C-telopeptide fragments (CTX) released in the supernatants, demonstrating the direct contribution of IL-17 in destruction. IL-17 and its producing T cells appear to contribute to the inflammatory process involved in the rheumatoid lesion.

Arthritis, Rheumatoid↗
PubMed2000

A combination of low doses of 17 beta-estradiol and norethisterone acetate prevents bone loss and normalizes bone turnover in postmenopausal women.

The effects of 17 beta-estradiol (E2) 1 mg combined with low doses of norethisterone acetate (NETA) on postmenopausal bone loss and turnover were investigated in a 2-year, randomized, double-masked, placebo-controlled trial. A total of 135 postmenopausal women with a lumbar spine bone mineral density (BMD) T-score between -2 and +2 were randomized to daily treatment with an oral tablet of either placebo, E2 1 mg/NETA 0.25 mg, or E2 1 mg/NETA 0.5 mg. Significant (p < 0.001) increases in BMD at the lumbar spine (L1-4) were observed with E2 1 mg/NETA 0.25 mg (5.2%) and E2 1 mg/NETA 0.5 mg (5.4%) compared with placebo (-0.9%). The total hip BMD increased significantly in the E2 1 mg/NETA 0.25 mg (3.1%) and E2 1 mg/NETA 0.5 mg groups (3.3%) compared with placebo. At the femoral trochanter, the increase in BMD in the E2 1 mg/NETA 0.5 mg group (6.3%) was significantly different from the placebo group (0.8%), while that in the E2 1 mg/NETA 0.25 mg group (3.3%) was not. No statistical differences were found between the active groups and placebo for the change in BMD at the femoral neck. Significant increases in BMD at the distal radius and total body were found for both E2 1 mg/NETA 0.25 mg (0.9% and 2.5%, respectively) and E2 1 mg/NETA 0.5 mg (2.1% and 3.0%, respectively) compared with placebo (-0.7% and 0.4%, respectively). At the end of the treatment, urinary pyridinoline type I collagen C-telopeptide had decreased by 65% and 60% in the E2 1 mg/NETA 0.25 mg and E2 1 mg/NETA 0.5 mg groups, respectively, while the mean serum concentrations of osteocalcin had decreased by 39% and 34%, bone-specific alkaline phosphatase by 32% and 29%, and C-terminal propeptide of type I collagen by 21% and 19% had decreased by 34-39%, 29-32%, and 19-21% in the E2 1 mg/NETA 0.25 mg and E2 1 mg/NETA 0.25 mg groups, respectively. In conclusion, combinations of E2 1 mg and NETA 0.25 or 0.5 mg prevent bone loss in postmenopausal women at the lumbar spine, hip, distal radius and total body, and normalize bone turnover.

Aged↗