Search PubMed⌕ Search

Biomedical subjects

C D Arnaud

Publications and source records attributed to C D Arnaud.

At least 19 recordsLinked to original sources
PubMed2003

Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis.

Daily treatment with hPTH (1-34) is associated with a significant increase in bone formation which results in large gains in lumbar spine bone mass. However, bone formation is known to occur on trabecular, endocortical and periosteal surfaces. The purpose of this study was to determine whether daily treatment with hPTH (1-34) for 1 year was associated with a change in vertebral cross-sectional area, or vertebral size, as measured by serial quantitative computed tomography scans. Fifty-one postmenopausal women treated chronically with both glucocorticoids and hormone replacement therapy (HRT) were randomized to either daily hPTH (1-34) for 1 year and HRT or to a control group treated with only HRT. Measurements of bone density of the spine were obtained every 6 months by dual-energy X-ray absorptiometry (DXA) and annually by QCT of the L1 and L2 vertebrae. Vertebral cross-sectional area (VCSA) was obtained from the QCT scans. In addition, we estimated the vertebral compressive strength (VSFOM, g(2)/cm(4) = trabecular BMD(2) x VCSA). After 1 year of hPTH (1-34) treatment, VCSA increased 4.8% (p < 0.001), and 1 year after treatment was discontinued VCSA was still 2.6% higher than the baseline value (p < 0.05). The control group had no change in VCSA. In addition, estimated vertebral compressive strength increased more than 200% over baseline levels in the hPTH (1-34) treatment group and no change was observed in the control group. In summary, daily treatment with hPTH (1-34) for 1 year increased vertebral size as measured by VCSA and this increase was maintained after hPTH (1-34) was discontinued. Since vertebral fracture risk is related to both bone size and bone mass, we cautiously speculate that the increase in vertebral size associated with hPTH (1-34) treatment is at least partially responsible for increased vertebral bone strength and reduction of fracture risk associated with this therapy in postmenopausal osteoporosis.

Absorptiometry, Photon↗
PubMed2001

Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

BACKGROUND: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS: We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS: New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). CONCLUSIONS: Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Bone Density↗
PubMed2000

Short-term increases in bone turnover markers predict parathyroid hormone-induced spinal bone mineral density gains in postmenopausal women with glucocorticoid-induced osteoporosis.

The purpose of this study was to test the ability of early changes in markers of bone turnover to predict subsequent changes in bone mineral density (BMD) induced by parathyroid hormone fragment, PTH (1-34), in postmenopausal osteoporotic women treated with estrogen and glucocorticoids. Forty-nine postmenopausal women with chronic, inflammatory diseases and BMD T-scores < or = -2.5 at the lumbar spine or femoral neck who were concurrently treated with estrogen > or = 1 year and prednisone 5-20 mg/day for > or = 1 year participated. Subjects were randomized to treatment with human PTH (1-34) 400 IU/day or to a control group for 1 year and followed for an additional year. Serum and urine were collected at baseline and 1, 3, 6, 9, 12, 18 and 24 months for measurement of bone alkaline phosphatase (BAP), osteocalcin (OC) and deoxypyridinoline (DPD). We constructed an Uncoupling Index (UI) from all three markers (UI = [ZBAP + Zoc]/2 -ZDPD, where the Z-score for each marker in each subject was calculated from the mean and standard deviation of the study population at baseline). BMD of the lumbar spine and hip was measured at baseline and every 6 months thereafter by dual-energy X-ray absorptiometry (DXA) and annually by quantitative computed tomography (QCT; spine only). BMD of the spine, but not hip (total, femoral neck or trochanter), and levels of all three markers increased significantly as a result of PTH treatment (p<0.01 compared with controls). The resorption response lagged behind that of formation as evidenced by a significant increase (p < 0.05) in the UI for the first 9 months of treatment. The UI values and changes from baseline to 1, 3 and 6 months in BAP, OC and DPD were correlated with the 12- and 24-month changes in spine BMD measured both with QCT and with DXA (Spearman's rank coefficients <0.76; p<0.05). Most PTH-treated subjects could be identified as biochemical responders by least significant change analysis. Following 1 month of therapy, BAP and OC identified 65% and 81% as responders, respectively. The responder rates were 79%, 79% and 75% for BAP, OC and DPD, respectively by 6 months. Responders exhibited a high level of diagnostic accuracy for predicting a gain in BMD (areas under the receiver operating characteristic curves exceeding 0.79 for QCT and 0.70 for DXA), but not the magnitude of the gain. These data suggest that serial bone marker measurements may be useful in identifying skeletal responders to an anabolic therapy, such as PTH, in estrogen-replete postmenopausal women with glucocorticoid-induced osteoporosis.

Aged↗
PubMed2000

Correlation of estradiol, parathyroid hormone, interleukin-6, and soluble interleukin-6 receptor during the normal menstrual cycle.

Rodent models suggest that estradiol deficiency promotes bone loss through increasing interleukin-6 (IL-6) activity. However, it is controversial as to whether these findings are applicable to humans. To evaluate estradiol-mediated modulation of IL-6 activity in relation to bone metabolism in humans, we measured serum IL-6, soluble interleukin-6 receptor (sIL-6R), estradiol (E2), progesterone, luteinizing hormone, follicle-stimulating hormone, intact parathyroid hormone (PTH), serum and urine Ca, and bone biochemical markers (serum bone-specific alkaline phosphatase, osteocalcin, and serum and urine deoxypyridinoline [Dpd]) across one menstrual cycle for 211 women. Neither IL-6 nor sIL-6R levels differed between the follicular phase (FP) and the luteal phases (LP). However, IL-6 was negatively correlated with E2 during the FP (p =0.003). Furthermore, IL-6 correlated positively with serum Ca over the entire cycle (p = 0.0091. Serum Ca correlated positively with serum (p = 0.040) and urine (p = 0.006) Dpd. PTH was significantly higher during the FP than in the LP (p = 0.004). PTH was negatively related to E2 (p = 0.002), serum Ca (p < 0.001), and urine Ca (p = 0.036), whereas it was positively correlated with IL-6 (p = 0.027). These data demonstrate that IL-6 and PTH fluctuate with E2, and serum II-6 is associated with PTH levels during the menstrual cycle. However, the role of 11-6 in bone remodeling during the normal menstrual cycle remains to be determined.

Adult↗
PubMed2000

Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial.

Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis. In this 24-month study, we report changes in bone turnover and bone mass after 12 months of daily injections of human parathyroid hormone 1-34 [hPTH(1-34)] and 12 months off treatment in postmenopausal women (mean age, 63 years) with osteoporosis treated with glucocorticoid and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy X-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SEM) change in BMD of the lumbar spine by QCT and DXA in the PTH group at 24 months was 45.9+/-6.4% and 12.6+/-2.2% (p < 0.001). The change in total hip and femoral neck BMD was not significant at 12 months but increased to 4.7+/-0.9% (p < 0.01) and 5.2+/-1.3% at 24 months, respectively, as compared with a relatively small change of 1.3+/-0.9% and 2.6+/-1.7% in the estrogen-only group. The mean percent differences in BMD of the lumbar spine by QCT and DXA between the groups at 24 months were 43.1% and 11.9%, respectively (p < 0.001). The mean percent differences over the estrogen-only group in hip BMD were 3.4% for total hip (p < 0.01) and 2.6% for femoral neck at 24 months. Biochemical markers of bone turnover increased to more than 150% during the first 6 months of therapy, remained elevated throughout the 12-month treatment period, and returned to baseline values within 6 months of discontinuing the PTH treatment. These results suggest that PTH dramatically increases bone mass in the lumbar spine and hip in postmenopausal women with glucocorticoid-induced osteoporosis who are taking hormone replacement therapy. However, the maximum effect of this anabolic agent on bone mass at the hip after 12 months of treatment requires at least 6-12 months after the PTH treatment is discontinued.

Absorptiometry, Photon↗
PubMed2000

Selective estrogen receptor modulators and postmenopausal health.

SERMs are a class of drugs with mixed estrogen agonist/antagonist effects that have great potential at targeting changes seen in the postmenopausal period. Raloxifene is effective in preventing bone loss and may prevent fractures in postmenopausal osteoporosis. It induces changes in lipoprotein concentrations that should be cardioprotective. It has no stimulatory effect on the uterus and is well tolerated. Raloxifene is an attractive alternative to HRT in preventing postmenopausal bone loss, especially for women that are more concerned about the risk of breast cancer or vaginal bleeding. Unanswered questions include raloxifene's effect on fracture incidence, cardiac events, and dementia; long-term safety data are also needed. Its potential role in the primary prevention of breast cancer also needs large, long-term studies. Tamoxifen has been used traditionally as adjuvant therapy for breast cancer, but new data indicate that it is effective in the primary prevention of breast cancer in women at increased risk. Its effects on bone and lipoproteins are attractive complementary effects when used in the subset of women at increased risk for breast cancer. New generations of SERMs are being developed that may have more potent estrogen agonist effects on bone and cardiovascular disease, or more potent antiestrogen effects, especially at the breast. There will likely be a selection of SERMs available, and the choice of SERM for a woman will be tailored to her specific issues and risk profile.

Breast Neoplasms↗
PubMed1999

Stable human calcitonin analogues with high potency on bone together with reduced anorectic and renal actions.

Various derivatives of human calcitonin have been synthesized and their biological characteristics compared with those of existing calcitonins. The acute effects of these analogues in reducing serum calcium levels and suppressing appetite were assessed in rats. A calcitonin analogue, PO-1 (CGNLSTCMLGKLSQELHKLQTYPQTAIGVGAP-NH2), having both the N- and C-terminal ten amino acid sequences those of human calcitonin, and the 12 amino acid central region that of salmon calcitonin, was found to have equal effectiveness with salmon calcitonin and elcatonin for reducing serum calcium levels. Strong hypocalcemic activity was also exhibited by PO-23 ([cyclo-Asp1, Lys7]-[des-Gly2]-[Leu8]-PO-1) and PO-29 ([Asp15, Asn17 , Phe19, His20]-PO-23). PO-23 was prepared by replacing the N-terminal Cys-Cys S-S bond of PO-1 with a ring structure composed of an Asp-Lys peptide bond to enhance physicochemical stability. PO-29 was prepared by modifying the central area of the PO-23 molecule to more closely mimic human calcitonin. When tested in vitro, human calcitonin analogues with a [cyclo-Asp1, Lys7] structure showed biological activities on osteoclast-like cells comparable to those of existing calcitonins (salmon calcitonin and elcatonin) in keeping with their relative potencies for in vivo hypocalcemic action. Acute anorectic activity in rats was strong with salmon calcitonin and elcatonin but relatively reduced with human calcitonin analogues having a [cyclo-Asp1, Lys7] structure. The activities of these analogues on kidney cells were also weaker than that of salmon calcitonin or elcatonin. These results suggest that stable human calcitonin analogues with a [cyclo-Asp1, Lys7] structure suppress bone resorption to a degree similar to that of salmon calcitonin or elcatonin with weaker activities on non-osseous tissues which might be related to adverse reaction.

Amino Acid Sequence↗
PubMed1999

Changes in bone resorption during the menstrual cycle.

To determine if the cyclic changes of female sex hormones during the menstrual cycle are related to changes in bone formation and resorption, we measured serum bone-specific alkaline phosphatase (BAP) and osteocalcin (OC) and bone resorption markers, serum and urine deoxypyridinoline (Dpyr), three times per week during one menstrual cycle in 20 healthy premenopausal women. Serum estradiol (E2) and progesterone (P) showed characteristic cyclic fluctuations. Serum Dpyr was higher during the follicular phase (FP) than in the luteal phase (p = 0.027). Serum BAP, OC, and urine Dpyr levels did not change substantially across the cycle. Serum Dpyr correlated negatively with serum E2 values measured 6 (p = 0.011) and 8 (p = 0.001) days earlier and with P measured concurrently (p = 0.033) 2 (p = 0.002), 4 (p = 0.003), and 6 (p = 0.014) days earlier. BAP correlated negatively with E2 measured 6 days earlier (p = 0.006). We found no statistically significant correlations of E2 or P with OC or urine Dpyr within women over their cycles. BAP was positively correlated with concurrent serum Dpyr (p = 0.015) during the menstrual cycle. Serum OC levels correlated inversely with age (rs = -0.48, p = 0.036). Women with higher mean urine Dpyr levels had higher mean serum OC levels (rs = 0.49, p = 0.033) and showed a trend toward lower hip bone mineral density (rs = -0.40, p = 0.078). We conclude that the low level of E2 and/or P observed during the FP of the normal menstrual cycle is associated with increased bone resorption. These relationships suggest that normal women experience monthly episodes of increased bone resorption from menarche to menopause.

Adult↗
PubMed1999

Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures.

To examine the ability of commercially available biochemical markers of bone formation and resorption to predict hip bone loss, we prospectively obtained serum and timed 2-h urine specimens from 295 women age 67 years or older who were not receiving estrogen replacement therapy. Serum was assayed for two markers of bone formation: osteocalcin (OC) and bone-specific alkaline phosphatase (BALP). Urine specimens were assayed for four markers of bone resorption: N-telopeptides (NTX), free pyridinolines (Pyr), free deoxypyridinoline (Dpyr), and C-telopeptides (CTX). Measurements of hip bone mineral density were made at the time the samples were collected and then repeated an average of 3.8 years later. Higher levels of all four resorption markers were, on average, significantly associated with faster rates of bone loss at the total hip, but not at the femoral neck. Women with OC levels above the median had a significantly faster rate of bone loss than women with levels below the median, but there was no significant association between levels of BALP and hip bone loss. The sensitivity and specificity of higher marker levels for predicting rapid hip bone loss was limited, and there was considerable overlap in bone loss rates between women with high and low marker levels. We conclude that higher levels of urine NTX, CTX, Pyr, Dpyr, and serum OC are associated with faster bone loss at the hip in this population of elderly women not receiving estrogen replacement therapy, but these biochemical markers have limited value for predicting rapid hip bone loss in individuals.

Aged↗
PubMed1998

Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial.

Corticosteroid-induced osteoporosis is the most common secondary cause of osteoporosis. We conducted a 12-mo, randomized clinical trial of human parathyroid hormone 1-34 (hPTH 1-34) in postmenopausal women (mean age was 63 yr) with osteoporosis who were taking corticosteroids and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy x-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SE) changes in BMD of the lumbar spine by QCT and DXA in the PTH group were 35+/-5.5% and 11+/-1.4%, respectively, compared with a relatively small change of 1.7+/-1.8% and 0+/-0.9% in the estrogen-only group. The differences in mean percentage between the groups at 1 yr were 33.5% for the lumbar spine by QCT (P < 0.001) and 9.8% for the lumbar spine by DXA (P < 0.001). The changes in the hip and forearm were not significantly different between or within the groups. During the first 3 mo of PTH treatment, markers of bone formation increased to nearly 150%, whereas markers of bone resorption increased only 100%, suggesting an early uncoupling of bone turnover in favor of formation. These results suggest that parathyroid hormone dramatically increases bone mass in the central skeleton of postmenopausal women with corticosteroid- induced osteoporosis who are taking hormone replacement.

Absorptiometry, Photon↗
PubMed1997

Not all postmenopausal women on chronic steroid and estrogen treatment are osteoporotic: predictors of bone mineral density.

Chronic steroid use results in osteoporosis, and postmenopausal women are believed to be at a high risk for steroid-induced bone loss. The purpose of this study was to determine predictors of bone mineral density (BMD) in postmenopausal women on both chronic steroid and hormone replacement therapy. Seventy-six postmenopausal women (> or = 3 years postmenopausal, > or = 2 years of steroid treatment of > or = 5 mg/day of prednisone, and > or 1 year of hormone replacement therapy) were recruited into this study. Measurements of BMD of the lumbar spine and femoral neck were obtained in all subjects. Risk factors for osteoporosis were obtained by questionnaire. Discriminant analysis was performed to determine predictors of BMD. Osteoporosis, defined by a T score of < -2.5, was present in the lumbar spine or femoral neck in 34 of the 76 subjects. Based on these criteria, women with osteoporosis were significantly older, were more years postmenopausal, and had a lower body mass index (BMI) than women who did not have osteoporosis. Predictors of osteoporosis for both the femoral neck and spine included a low BMI (P < 0.05), more years postmenopausal (P < 0.01), and more years on steroids (P < 0.01). Low BMI was the only significant predictor of osteoporosis in the lumbar spine (P < 0.05), whereas for the femoral neck both years on steroids (P < 0.05) and BMI (P < 0.05) were significant predictors of low BMD. In summary, not all postmenopausal women on chronic steroid and hormone replacement therapy are osteoporotic but a low BMI, more years on steroids, and more years postmenopausal were significant predictors of osteoporosis in these subjects.

Absorptiometry, Photon↗
PubMed1996

Osteoporosis: using 'bone markers' for diagnosis and monitoring.

Bone is continuously resorbed and formed in the process of remodeling. Osteoporosis results when bone loss is sufficient to cause increased risk of fracture. High rates of bone turnover can be identified by measuring biochemical byproducts of resorption and formation. Collagen crosslinks and associated peptides measured in urine are newly recognized markers for bone resorption. Bone-specific alkaline phosphatase and osteocalcin are serum markers for bone formation. The clinical utility of these new techniques is two-fold: to identify adults at high risk of osteoporosis so that preventive therapy can be instituted, and to provide noninvasive, sensitive tools for monitoring clinical course and effect of therapy.

Aged↗
PubMed1993

An integrated view of the role of the endocrine system in the genesis of the osteoporosis associated with aging.

Estrogen deficiency is the major determinant of increased bone resorption and bone loss occurring in early menopause (first 5-6 years). The increased bone resorption is probably caused by the release of immune system cytokines such as IL-1, IL-6 and TNF by osteoblasts, the biosynthesis of which is no longer suppressed by estrogen. PTH secretion, although decreased in early menopause, may also contribute to increased bone destruction because of the presence of cytokines such as IL-1 and TNF which increase the sensitivity of bone to the resorptive effects of PTH. For the same reasons, the bone-destructive effects of increased serum levels of PTH occurring in the late menopause may be exaggerated.

Aging↗
PubMed1993

Menopause without symptoms: the endocrinology of menopause among rural Mayan Indians.

OBJECTIVE: Our purpose was to determine the characteristics of menopause among Mayan women who did not have menopausal symptoms. STUDY DESIGN: A cross-sectional study of Mayan women from Chichimila, Mexico, was performed. Demographic information, history and physical examination, hormone concentrations, and radial bone density measurement were obtained. RESULTS: Fifty-two postmenopausal women were compared with 26 premenopausal women. Menopause occurred at 44.3 +/- 4.4 years. None of the women admitted to hot flushes and did not recall significant menopausal symptoms. Hormone levels included elevated follicle-stimulating hormone (66.6 +/- 29 mlU/ml), low estradiol and estrone (9.4 +/- 8.3 and 13.3 +/- 7.8 pg/ml), estrone greater than estradiol levels, normal levels of testosterone and androstenedione (0.17 +/- 0.14 and 0.31 +/- 0.17 ng/ml). Bone mineral density declined with age, but height did not. Clinical evidence of osteoporosis was not detected. CONCLUSIONS: Lack of symptoms during the menopausal transition is not attributable to a difference in endocrinology. Postmenopausal Mayan women are estrogen deprived and experience age-related bone demineralization but do not have a high incidence of osteoporotic fractures.

Adult↗
PubMed1992

Two homologs of the Drosophila polarity gene frizzled (fz) are widely expressed in mammalian tissues.

The frizzled (fz) locus of Drosophila encodes a protein (Fz) with a seven-transmembrane-domain profile characteristic of G-protein-coupled receptors. In Drosophila, genetic evidence suggests that Fz functions to transmit and transduce polarity signals in epidermal cells during hair and bristle development. We have isolated from a UMR 106 rat osteosarcoma cell library a cDNA (fz-1) encoding a predicted 641-residue protein (Fz-1) with 46% homology with Drosophila Fz. We also identified a second cDNA (fz-2) encoding a protein (Fz-2) of 570 amino acids that is 80% homologous with Fz-1, with divergence most evident in the extracellular domains. Southern blots of rat genomic DNA indicated that fz-1 and fz-2 represent distinct genes. Northern analysis revealed the presence of a single fz-1 mRNA (4.7 kilobases) and two fz-2 mRNAs (2.5 and 4.5 kilobases) in rat tissues. The fz-1 and fz-2 genes are widely expressed in rat tissues with the highest steady-state levels of mRNA in kidney, liver, heart, uterus, and ovary. fz-1 and -2 mRNA levels were greater in neonatal than in corresponding adult tissues. Treatment of UMR 106 cells with bone resorbing agents including parathyroid hormone, epidermal growth factor, and 1,25-dihydroxyvitamin D3 produced increases in fz-1 and -2 mRNA levels. We suggest that hormonal induction of Fz proteins in osteoblasts serves to promote intercellular signaling required for functional responses such as increased bone resorption. Fz-1 and Fz-2 may represent products of a gene family whose members serve as transducers or intercellular transmitters of signals required for normal morphogenesis and/or differentiated function in diverse tissues.

Amino Acid Sequence↗
PubMed1990

Desensitization of parathyroid hormone receptors on cultured bone cells.

Administration of excessive amounts of parathyroid hormone (PTH) in the treatment of osteoporosis can reverse the beneficial effects of a low-dose, intermittent regime. To investigate the direct actions and the possible cellular mechanisms of PTH in inducing desensitization of PTH receptors, we studied the effects of desensitization on rat osteoblastic UMR-106 cells. When the osteoblasts were preincubated with bPTH-(1-34), complete refractoriness to a subsequent challenge with the hormone developed within 1 h and at hormone concentrations as low as 5 nM. When osteoblasts thus desensitized were incubated in hormone-free medium, recovery of the cAMP responses began within 2 h and reached maximum after 16 h. Cycloheximide did not affect the process of desensitization. [Nle8,Nle18,Tyr34]bPTH-(3-34)amide significantly impaired the desensitization process by PTH-(1-34) but did not have stimulatory effect on cAMP responses. No significant heterologous desensitization was obvious after preincubation with isoprenaline (50 microM), prostaglandin E1 (50 microM), or prostaglandin E2 (50 microM) for 2 h. Binding experiments with [125I]PLP-(1-36)amide after desensitization revealed that there was an approximate twofold decrease in receptor affinities as analyzed by Scatchard analysis, showing that the decrease in affinity was prominent in the process of desensitization. When the cells were treated with monensin during desensitization, PTH challenge after desensitization produced significantly lower cyclic AMP responses. Recovery after desensitization occurred over a period of 16 h. Inclusion of monensin, but not cycloheximide, impaired the recovery. The results show that homologous desensitization of rat osteoblasts to PTH is brought about by the occupancy of receptors by PTH-(1-34) but not by cAMP generation itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic AMP↗