PubMed Health⌕ Search

Biomedical subjects

K H Lau

Publications and source records attributed to K H Lau.

At least 19 recordsLinked to original sources
PubMed2006

Dissociation energies of the Cu and Ag monohalides and of Ni monofluoride.

Gaseous isomolecular equilibria of the type CuX + Ag = Cu + AgX, where X = F, Cl, Br, and I, were studied by effusion-beam mass spectrometry at elevated temperatures, and the differences between the dissociation energies of the CuX and AgX molecular species were determined with relatively high accuracy from thermochemical analysis of the equilibrium data. Analysis of literature data, plus new information on AgBr, yielded accurate values of D degrees 0 in kcal mol(-1) for CuF (102.0), AgCl (74.4), AgBr (66.4), and AgI (59.7), from which values were derived for AgF (81.5), CuCl (89.6), CuBr (79.2), and CuI (69.4), all +/-1 kcal mol(-1). The result is a consistent set of dissociation energies for all eight of the Cu and Ag monohalides that will be useful in checking the reliability of quantum chemical calculations for these molecular species containing elements of increasing atomic number. Also, the isomolecular exchange equilibrium between CuF and NiF was studied in a similar fashion, leading to D degrees 0(NiF) = 104.4 +/- 1.4 kcal mol(-1).

Journal Article↗
PubMed2005

Composition and thermochemistry of silver bromide vapor.

The mole fractions of AgBr and Ag3Br3 in the saturated vapor at 840 K have been evaluated from the vapor mass spectrum, by comparison with the corresponding spectrum of AgCl vapor, where the monomer/trimer ratio is known accurately from vapor molecular weight measurements. Combination of these results with new measurements of the vapor pressure of molten AgBr by the torsion-effusion method in the range 805-936 K yielded the third law enthalpies of vaporization and the standard enthalpies of formation DeltafH degrees 298(AgBr, g) = 27.8 +/- 0.3 kcal mol(-1) and DeltafH degrees 298(Ag3Br3, g) = -19.0 +/- 1 kcal mol(-1). The dissociation energy, D degrees 0(AgBr), is found to be 66.4 +/- 0.3 kcal mol(-1), or 2.88 +/- 0.01 eV, some 3.5-5 kcal mol(-1) lower than previous literature values. Approximate thermochemical stabilities of the dimer species Ag2Cl2 and Ag2Br2 have also been evaluated.

Journal Article↗
PubMed2005

Thermochemical properties of the gaseous bromo-iodides of Dy and of the Na-Dy tetrahalo complexes.

The gaseous mixed dimers NaDyBr4 and NaDyI4 and the bromo-iodide species DyBrI, DyBr2I, DyBrI2, NaDyBr3I, NaDyBr2I2, and NaDyBrI3 were generated in an effusion cell reactor at elevated temperatures using several different source configurations and were identified by mass spectrometry. A number of gaseous equilibria involving these species were studied, and thermochemical properties were derived with the aid of thermal functions based on estimated molecular constants. Enthalpies of formation of NaDyBr4 and NaDyI4 are compared with values in the literature, while results for the bromo-iodides are in close accord with values interpolated from data on the pure metal bromides and iodides.

Journal Article↗
PubMed2001

Development of an MFG-based retroviral vector system for secretion of high levels of functionally active human BMP4.

We sought to develop a retroviral vector system that would produce secretion of high levels of bone morphogenetic protein (BMP)-4 by optimizing the expression construct and developing an improved retroviral vector. Replacement of the propeptide domain of BMP4 with that of BMP2 increased the secretion level of mature BMP4 protein in transduced cells. The intact BMP2 pro-peptide sequence was essential, as deletion of a small part of the propeptide sequence of BMP2 from the BMP2/4 hybrid construct diminished BMP4 expression and secretion. Addition of a hemaglutinin tag to the carboxy terminus of BMP4 abolished the bioactivity of secreted BMP4. Transduction of rat marrow stromal cells (and fibroblasts) with an MFG-based retroviral vector pseudotyped with VSV-G envelope containing this BMP2/4 hybrid expression construct led to secretion of very high levels of mature BMP4 in conditioned medium (up to 1 microg/10(6) cells/24 hours). The secreted BMP4 was biologically active, as it induced alkaline phosphatase expression in C2C12 cells. The transduced rat marrow stromal cells expressing mature BMP4 induced de novo ectopic bone formation in syngenic immune-competent rats. We have developed an MFG-based retroviral vector system that causes secretion of high levels of functionally active human BMP4 protein.

Animals↗
PubMed2001

Differential effects of bacterial toxins on mitogenic actions of sodium fluoride and those of aluminum fluoride in human TE85 osteosarcoma cells.

This study compared the effects of cholera toxin (CTX) and pertussis toxin (PTX) on the actions of sodium fluoride (NaF) and those of aluminum fluoride (AlF3) on cell proliferation and differentiation, as well as tyrosine phosphorylation level of mitogen activated protein kinase (MAPK) in human bone cells. NaF and AlF3 each significantly stimulated the proliferation of human TE85 osteosarcoma cells, increased cellular alkaline phosphatase (ALP) activity, and increased MAPK tyrosine phosphorylation level. CTX completely blocked the bone cell anabolic activities of both NaF and AlF3. While PTX (2 ng/ml) inhibited the bone cell actions of NaF, it had no significant effect on those of AlF3. Both CTX and PTX completely blocked the stimulatory action of AlF3 on MAPK tyrosine phosphorylation, but neither toxin had an effect on the action of NaF on MAPK tyrosine phosphorylation. In conclusion, PTX and CTX had contrasting effects on the anabolic bone cell actions of NaF and AlF3 actions. These findings argue against the hypothesis that the osteogenic activity of NaF is mediated via the formation of AlF3 in human TE85 osteosarcoma cells.

Alkaline Phosphatase↗
PubMed2001

Antisense oligodeoxynucleotide evidence that a unique osteoclastic protein-tyrosine phosphatase is essential for osteoclastic resorption.

This study tested the hypothesis that a unique osteoclastic transmembrane protein tyrosine phosphatase (PTP-oc) is involved in osteoclastic resorption by determining whether suppression of PTP-oc expression with a specific phosphorothioated 20-mer PTP-oc antisense oligodeoxynucleotide (oligo) would inhibit basal, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-stimulated, and PTH-stimulated osteoclastic resorption. Treatment of rabbit osteoclasts with 1 microM of the antisense oligo for up to 4 days showed a time-dependent reduction in PTP-oc protein level, indicating that this PTP-oc antisense oligo was effective. To assess the effect of PTP-oc antisense oligo on osteoclastic resorption, rabbit osteoclasts were pretreated for 3 days with 1 microM of the antisense, a scramble oligo, or vehicle, respectively, followed by a 3-day treatment with vehicle, 10 nM of 1,25(OH)2D3, or 10 nM of parathyroid hormone (PTH). 1,25(OH)2D3 and PTH each alone increased PTP-oc cellular level and stimulated resorptive activity of rabbit osteoclasts. The antisense oligo treatment, but not the scramble oligo, decreased the basal and the stimulated resorption activity and reduced the PTP-oc protein level. Treatment with the PTP-oc antisense oligo, but not the scramble oligo, also markedly increased the Y527 phosphorylation level of c-src in rabbit osteoclasts. In conclusion, these results provide the first antisense oligo evidence that PTP-oc plays an essential role in osteoclastic resorption.

Animals↗
PubMed2001

Bone loss in patients with untreated chronic obstructive pulmonary disease is mediated by an increase in bone resorption associated with hypercapnia.

This study sought to determine whether the bone loss in untreated chronic obstructive pulmonary disease (COPD) is associated with hypercapnia and/or respiratory acidosis. Bone mineral density (BMD) measured at the distal forearm of the nondominant arm (with peripheral quantitative computed tomography [pQCT]) and serum markers of bone turnover were determined in 71 male patients with untreated COPD and 40 healthy male subjects who matched the patients in age, weight, and body mass index (BMI). The COPD patients, compared with controls, had reduced pulmonary functions, lower arterial pH, and elevated arterial partial pressure of CO2 (PCO2) The BMD (in T score) was significantly lower in COPD patients than that in control subjects (-1.628 +/- 0.168 vs. -0.058 +/- 0.157; p < 0.001). The BMD of COPD patients correlated positively with arterial pH (r = 0.582; p < 0.001), negatively with PCO2 (r = -0.442; p < 0.001), and negatively with serum cross-linked telopeptide of type I collagen (ICTP), a bone resorption marker (r = -0.444; p < 0.001) but not with serum osteocalcin, a bone formation marker. Serum ICTP, but not osteocalcin, correlated with PCO2 (r = 0.593; p < 0.001) and arterial pH (r = -0.415; p < 0.001). To assess the role of hypercapnia, COPD patients were divided into the hypercapnic (PCO2 > 45 mm Hg; n = 35) and eucapnic (PCO2 = 35-45 mm Hg) group (n = 36). Patients with hypercapnia had lower BMD, lower arterial pH, and higher serum ICTP than did patients with eucapnia. Arterial pH and serum ICTP of eucapnic patients were not different from those of controls. To evaluate the role of uncompensated respiratory acidosis, COPD patients with hypercapnia were subdivided into those with compensatory respiratory acidosis (pH > or = 7.35; n = 20) and those with uncompensated respiratory acidosis (pH < 7.35; n = 15). The BMD and serum ICTP were not different among the two subgroups. In conclusion, this study presents the first associative evidence that the bone loss in COPD is at least in part attributed to an increased bone resorption that is associated primarily with hypercapnia rather than uncompensated respiratory acidosis.

Acidosis, Respiratory↗
PubMed2001

Dietary boron supplementation enhances the effects of estrogen on bone mineral balance in ovariectomized rats.

The present study investigated whether boron would enhance the action of 17beta-estradiol (E2) or parathyroid hormone (PTH) on bone mineral balance in ovariectomized (OVX) rats. Forty-three days after OVX, the rats were treated for 5 wk with vehicle, boron (5 ppm as boric acid), E2 (30 microg/kg/d, sc), PTH (60 microg/kg/d, sc), or a combination of boron and E2 or PTH. Bone mineral balance was assessed by measuring apparent absorption, excretion, and retention of calcium (Ca), phosphorus (P), and magnesium (Mg). Serum Ca, P, Mg, and osteocalcin were also measured in this experiment. Boron alone had no effects on food consumption, weight gain, bone mineral balance, and serum levels of Ca, P, Mg, and osteocalcin. E2 alone increased serum P and Mg and decreased serum osteocalcin, but it had no effect on bone mineral balance. The combination of boron and E2 markedly improved apparent absorption of Ca, P, and Mg. In addition, the combination treatment increased the apparent retention of Ca and Mg (but not P) and also increased serum Ca and Mg but not serum P. On the other hand, boron cotreatment did not prevent the E2-induced reduction in serum osteocalcin in OVX rats. PTH alone significantly increased serum Ca, P, Mg, and osteocalcin concentrations, although it had no effect on bone mineral balance. Contrary to the boron-E2 combination treatment, the combination of boron and PTH did not enhance bone mineral balance. However, inasmuch as boron-PTH cotreatment did not enhance the stimulatory action of PTH on serum Ca, P, and osteocalcin, boron completely abolished the stimulatory effect of PTH on serum Mg. In conclusion, we have demonstrated for the first time that although boron by itself has no effect on bone mineral homeostasis, it appears to have synergistic enhancing effects on the action of E2 on Ca and Mg homeostasis in OVX rats.

Animals↗
PubMed2001

Dietary boron supplementation enhanced the action of estrogen, but not that of parathyroid hormone, to improve trabecular bone quality in ovariectomized rats.

This study investigated whether boron would enhance the ability of 17beta-estradiol (E2) or parathyroid hormone (PTH) to improve bone quality in ovariectomized OVX rats. Adult OVX rats were treated for 5 wk with vehicle, boron (5 ppm as boric acid), E2 (30 microg/kg/d, sc), PTH (60 microg/kg/d, sc), or a combination of boron and E2 or PTH, respectively. The E2 treatment corrected many adverse effects of OVX on bone quality, increased bone Ca, P, and Mg contents, and decreased trabecular plate separation. Dietary boron supplementation had no effects on these bone parameters in OVX rats. When OVX rats were treated with boron and E2 together, trabecular bone volume (Tb.BS/TV) and plate density were increased significantly more than that caused by E2 alone. The boron and E2 combination also increased trabecular bone surface (Tb.BV/TV) and decreased trabecular plate separation in OVX rats. In contrast, whereas daily PTH injection also increased bone Ca, Mg, and P contents, Tb.BV/TV, Tb.BS/TV, trabecular plate density and thickness, and decreased trabecular plate separation in OVX rats, the combination of boron and PTH had no additional improvement in bone quality over that achieved by PTH alone. In summary, this study shows for the first time that boron enhanced the action of E2, but not that of PTH, to improve trabecular bone quality in OVX rats.

Animals↗
PubMed2000

Evidence that the interaction between insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-4 is essential for the action of the IGF-II-dependent IGFBP-4 protease.

A variety of human cell types, including human osteoblasts (hOBs), produce an IGFBP-4 protease, which cleaves IGFBP-4 in the presence of IGF-II. Recently, the pregnancy-associated plasma protein (PAPP)-A has been determined to be the IGF-II-dependent IGFBP-4 protease produced by human fibroblasts. This study sought to define the mechanism by which IGF-II enhances IGFBP-4 proteolysis. Addition of PAPP-A antibody blocked the IGFBP-4 proteolytic activity in hOB conditioned medium (CM), suggesting that PAPP-A is the major IGFBP-4 protease in hOB CM. Pre-incubation of IGFBP-4 with IGF-II, followed by removal of unbound IGF-II, led to IGFBP-4 proteolysis without further requirement of the presence of IGF-II in the reaction. In contrast, prior incubation of the partially purified IGFBP-4 protease from either hOB CM or human pregnancy serum with IGF-II did not lead to IGFBP-4 proteolysis unless IGF-II was re-added to the assays. To further confirm that the interaction between IGF-II and IGFBP-4 is required for IGFBP-4 protease activity, we prepared IGFBP-4 mutants, which contained the intact cleavage site (Met135-Lys136) but lacked the IGF binding activity, by deleting the residues Leu72-His74 in the IGF binding domain or Cys183-Glu237 that contained an IGF binding enhancing motif. The IGFBP-4 protease was unable to cleave these IGFBP-4 mutants, regardless of whether or not IGF-II was present in the assay. Conversely, an IGFBP-4 mutant with His74 replaced by an Ala, which exhibited normal IGF binding activity, was effectively cleaved in the presence of IGF-II. Taken together, these findings provided strong evidence that the interaction between IGF-II and IGFBP-4, rather than the direct interaction between IGF-II and IGFBP-4 protease, is required for optimal IGFBP-4 proteolysis.

Antibodies↗
PubMed1999

Vitamin D therapy of osteoporosis: plain vitamin D therapy versus active vitamin D analog (D-hormone) therapy.

Normal intestinal calcium (Ca) absorption is an essential feature of bone homeostasis. As with many other organ systems, intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of senile osteoporosis in the elderly. This abnormality leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid hormone (PTH) and an increase in bone resorption. Secondary hyperparathyroidism due to poor intestinal Ca absorption has been implicated not only in senile osteoporosis but also in age-related bone loss. Accordingly, in population-based studies, there is a gradual increase in serum PTH from about 20 years of age onward, which constitutes a maximum increase at 80 years of age of 50% of the basal value seen at 30 years of age. The cause of the increase in PTH is thought to be partly due to impaired intestinal Ca absorption that is associated with aging, a cause that is not entirely clear but at least in some instances is related to some form of vitamin D deficiency. There are three types of vitamin D deficiency: (1) primary vitamin D deficiency, which is due to a deficiency of vitamin D, the parent compound; (2) a deficiency of 1,25(OH)(2)D(3) resulting from decreased renal production of 1,25(OH)(2)D(3); and (3) resistance to 1,25(OH)(2)D(3) action owing to decreased responsiveness to 1, 25(OH)(2)D(3) of target tissues. The cause for the resistance to 1, 25(OH)(2)D(3) could be related to the finding that the vitamin D receptor level in the intestine tends to decrease with age. All three types of deficiencies can occur with aging, and each has been implicated as a potential cause of intestinal Ca malabsorption, secondary hyperparathyroidism, and senile osteoporosis. There are two forms of vitamin D replacement therapies: plain vitamin D therapy and active vitamin D analog (or D-hormone) therapy. Primary vitamin D deficiency can be corrected by vitamin supplements of 1000 U a day of plain vitamin D whereas 1,25(OH)(2)D(3) deficiency/resistance requires active vitamin D analog therapy [1, 25(OH)(2)D(3) or 1alpha(OH)D(3)] to correct the high serum PTH and the Ca malabsorption. In addition, in the elderly, there are patients with decreased intestinal Ca absorption but with apparently normal vitamin D metabolism. Although the cause of poor intestinal Ca absorption in these patients is unclear, these patients, as well as all other patients with secondary hyperparathyroidism (not due to decreased renal function), show a decrease in serum PTH and an increase in Ca absorption in response to therapy with 1, 25(OH)(2)D(3) or 1alpha(OH)D(3). In short, it is clear that some form of vitamin D therapy, either plain vitamin D or 1,25(OH)(2)D(3) or 1alpha(OH)D(3), can be used to correct all types of age-dependent impairments in intestinal Ca absorption and secondary hyperparathyroidism during aging. However, from a clinical standpoint, it is important to recognize the type of vitamin D deficiency in patients with senile osteoporosis so that primary vitamin D deficiency can be appropriately treated with plain vitamin D therapy, whereas 1,25(OH)(2)D(3) deficiency/resistance will be properly treated with 1,25(OH)(2)D(3) or 1alpha(OH)D(3) therapy. With respect to postmenopausal osteoporosis, there is strong evidence that active vitamin D analogs (but not plain vitamin D) may have bone-sparing actions. However, these effects appear to be results of their pharmacologic actions on bone formation and resorption rather than through replenishing a deficiency.

Aging↗
PubMed1999

Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth.

High-density C3H/HeJ (C3H) and low-density C57BL/6J (B6) mice, with femoral bone density differing by 50%, were chosen as a model to investigate the mechanisms controlling peak bone density and to map peak bone density genes. The present longitudinal study was undertaken to further establish the bone biologic phenotypes of these two inbred strains of mice. To evaluate phenotypic differences in bone formation parameters in C3H and B6 mice between the ages of 6 and 26 weeks, undecalcified ground sections from the diaphyses of the tibia and femur were prepared from mice receiving two injections of tetracycline. Histomorphometric analyses revealed that the cortical bone area was significantly greater (16%-56%, p < 0.001) in both the femur and tibia of the C3H mice than in the B6 mice at all timepoints. This difference in cortical bone area was due to significantly smaller medullary areas in the C3H mice than in the B6 mice. The bone formation rates (BFR) at the endosteum in both the femur and tibia were significantly greater (28%-117%,p < 0.001) in the young C3H mice (6-12 weeks old) than in B6 mice. The higher bone formation in C3H mice was associated with higher values of the bone mineral apposition rate (25%-94%, p < 0.001), and was not associated with higher values of the forming surface length as measured by tetracycline label length. Similar interstrain differences in mineral apposition and bone formation rates were observed in the periosteum of the femur and tibia. In conclusion, the greater bone area in the high-density C3H mice vs. the low-density B6 mice was, in part, due to the greater periosteal and endosteal bone formation rates during growth in the C3H mice. Because the C3H and B6 mice were maintained under identical environmental conditions (diet, lighting, etc.), the observed interstrain differences in bone parameters were the result of the action of genetic factors. Consequently, these two inbred strains of mice are suitable as a model to identify genetic factors responsible for high bone formation rates.

Animals↗
PubMed1998

Differential effects of two protein tyrosine kinase inhibitors, tyrphostin and genistein, on human bone cell proliferation as compared with differentiation.

Protein tyrosyl phosphorylation is a key determinant of cell proliferation and differentiation. The aim of this study was to test the hypothesis that the signal transduction pathway(s) responsible for human bone cell proliferation may involve different groups of protein tyrosine kinase (PTKs) as compared with that for differentiation. To achieve this, we investigated the effects of two structurally different PTK inhibitors, viz, tyrphostin A51 and genistein, on the proliferation ([3H]thymidine incorporation) and differentiation [alkaline phosphatase (ALP) specific activity and collagen synthesis] of two normal human bone cell types: mandible-derived and vertebra-derived bone cells. Tyrphostin A51 and genistein each markedly reduced cellular tyrosyl phosphorylation level (assessed by Western analysis using a commercial anti-phosphotyrosine antibody and the enhanced chemiluminescence detection assay), confirming that these two effectors are potent PTK inhibitors in human bone cells. Regarding bone cell proliferation, tyrphostin A51 (5-30 microM) caused, a dose-dependent inhibition of basal [3H]thymidine incorporation of both human bone cell types. In contrast, genistein (5-20 microM), not only did not inhibit, but significantly stimulated [3H]thymidine incorporation of these same cell types in a dose-dependent, biphasic manner, with the optimal stimulatory dose between 10 and 20 microM. These effects on cell proliferation were confirmed by cell number counting. In addition, whereas the mitogenic activity of 10 ng/ml epidermal growth factor (EGF) on human mandible-derived bone cells was completely abolished by 5-30 microM tyrphostin A51, genistein at 5-30 microM enhanced the EGF-induced bone cell proliferation in an additive manner. With respect to bone cell differentiation, tyrphostin A51 and genistein each significantly increased basal ALP specific activity and collagen synthesis in human bone cells. In summary, (1) PTKs are involved in human bone cell proliferation and differentiation; (2) tyrphostin A51 inhibited both basal and EGF-induced cell proliferation, thus tyrphostin-sensitive PTKs are involved in basal and EGF-induced human bone cell proliferation; (3) genistein stimulated basal proliferation and enhanced EGF-mediated cell proliferation, suggesting that genistein-sensitive PTKs may play an inhibitory role in human bone cell proliferation; and (4) these differential effects of PTK inhibitors on human bone cell proliferation and differentiation are independent of basal differentiation status of the cells.

Alkaline Phosphatase↗
PubMed1998

Effects of calcium depletion and repletion on serum insulin-like growth factor I and binding protein levels in weanling rats.

Previous studies in a weanling rat model indicated that dietary calcium depletion not only stimulated osteoclastic resorption but also inhibited bone formation. The present study sought to test whether the depletion-associated inhibition of bone formation is related to a reduction in serum insulin-like growth factor-I (IGF-I) and/or an increase in its binding proteins (IGFBPs). Twenty male weanling rats were divided into two weight-matched groups. The study group was subjected to a semisynthetic diet deficient in calcium (0.02% calcium) for 28 days, while the control group was pair-weighed on the same diet but containing 0.62% calcium. After the depletion phase, all rats were fed the same calcium-containing diet for an additional 14 days. Serum samples were obtained from each animal on a weekly basis and assayed for IGF-I and IGFBPs. During depletion, there was no statistically significant difference in serum IGF-I level between the study group and the control group. In contrast, the study group showed a statistically significant increase in several serum IGFBPs with apparent molecular size of 30-38 kD (IGFBP-3), 26-28 kD (IGFBP-1, -2, -5, and/or -6), and 24-25 kD (IGFBP-4), respectively, compared to the control group. There was no difference in nutritional intakes between the two groups of rats during depletion. During repletion, there was also no significant difference in serum IGF-I level between the control and study group. However, during the first 7 days of repletion, serum IGFBP-3 and the 26-28 kD IGFBP of the study group was significantly less than those of the control group, which then returned to the control level after 2 weeks of repletion. In summary: (1) calcium depletion in weanling rats increased several serum IGFBPs without an effect on IGF-I; and (2) calcium repletion induced an acute reduction in serum IGFBP-3. In conclusion, these findings represent the first evidence that the depletion-related inhibition of bone formation in the rat may be associated with an increase in several serum IGFBPs, which may act to inhibit the osteogenic actions of IGFs.

Animals↗
PubMed1998

Effects of short-term calcium depletion and repletion on biochemical markers of bone turnover in young adult women.

The skeletal responses to calcium depletion and repletion in rodents have been well characterized, but those in humans are poorly understood. The present study sought to evaluate the effects of short term dietary calcium depletion and repletion on biochemical markers of bone turnover in 15 young Caucasian women (age, 21-30 yr). The study contained 3 phases: 1) 5 days of a regular diet containing more than 800 mg/day calcium to establish baseline values (baseline phase), 2) 22 days of a restricted diet containing less than 300 mg/day calcium (depletion phase), and 3) 7 days of a normal diet containing more than 800 mg/day calcium (repletion phase). Serum and urine samples were obtained from each subject during the baseline phase; on the first, second, and last days of the depletion phase; and on the third and last days of the repletion phase. Serum levels of calcium, PTH, 1,25-dihydroxyvitamin D3, osteocalcin, and C-terminal type I procollagen peptide (PICP) and urinary levels of calcium and deoxypyridinoline were determined. Serum and urinary calcium levels were significantly reduced, and serum PTH and 1,25-dihydroxyvitamin D3 levels were markedly increased during depletion. These changes were completely reversed after 1 week of repletion. Depletion also rapidly and significantly increased the urinary deoxypyridinoline level, indicating increased bone resorption. The increase also returned rapidly to baseline upon repletion. Calcium depletion had contrasting effects on bone formation markers; whereas depletion significantly reduced the serum PICP level, it significantly increased serum osteocalcin level. Past histomorphometric studies in rodents indicated that the number of mature but inactive osteoblasts was increased during depletion despite an inhibition of bone formation. Thus, it is speculated that although the reduction in serum PICP reflected the depletion-associated inhibition of bone formation, the increase in serum osteocalcin could represent this depletion-related increase in osteoblast number. During repletion, serum osteocalcin remained elevated above baseline. PICP recovered from its depressed level and increased above baseline, a finding consistent with past histomorphometric findings of increased bone formation during repletion. In summary, this study confirms that 1) a short calcium depletion period produces calcium stress in young women, which leads to rapid stimulation of bone resorption and inhibition of bone formation; and 2) a subsequent calcium repletion period could lead to a compensatory increase in bone formation. In conclusion, the skeletal responses to calcium depletion/ repletion in young women may be similar to those in rodents.

Adult↗
PubMed1998

Daily oral magnesium supplementation suppresses bone turnover in young adult males.

This study examined the effects of daily oral magnesium (Mg) supplementation on bone turnover in 12 young (27-36 yr old) healthy men. Twelve healthy men of matching age, height, and weight were recruited as the control group. The study group received orally 15 mmol Mg (Magnosolv powder, Asta Medica) daily in the early afternoon with 2-h fasting before and after Mg intake. Fasting blood and second void urine samples were collected in the early morning on days 0, 1, 5, 10, 20, and 30, respectively. Total and ionized Mg2+ and calcium (Ca2+), and intact PTH (iPTH) levels were determined in blood samples. Serum biochemical markers of bone formation (i.e. C-terminus of type I procollagen peptide and osteocalcin) and resorption (i.e. type I collagen telopeptide) and urinary Mg level adjusted for creatinine were measured. In these young males, 30 consecutive days of oral Mg supplementation had no significant effect on total circulating Mg level, but caused a significant reduction in the serum ionized Mg+ level after 5 days of intake. The Mg supplementation also significantly reduced the serum iPTH level, which did not appear to be related to changes in serum Ca2+ because the Mg intake had no significant effect on serum levels of either total or ionized Ca2+. There was a strong positive correlation between serum iPTH and ionized Mg2+ (r = 0.699; P < 0.001), supporting the contention that decreased serum iPTH may be associated with the reduction in serum ionized Mg2+. Mg supplementation also reduced levels of both serum bone formation and resorption biochemical markers after 1-5 days, consistent with the premise that Mg supplementation may have a suppressive effect on bone turnover rate. Covariance analyses revealed that serum bone formation markers correlated negatively with ionized Mg2+ (r = -0.274 for type I procollagen peptide and -0.315 for osteocalcin), but not with iPTH or ionized Ca2+. Thus, the suppressive effect on bone formation may be mediated by the reduction in serum ionized Mg2+ level (and not iPTH or ionized Ca2+). In summary, this study has demonstrated for the first time that oral Mg supplementation in normal young adults caused reductions in serum levels of iPTH, ionized Mg2+, and biochemical markers of bone turnover. In conclusion, oral Mg supplementation may suppress bone turnover in young adults. Because increased bone turnover has been implicated as a significant etiological factor for bone loss, these findings raise the interesting possibility that oral Mg supplementation may have beneficial effects in reducing bone loss associated with high bone turnover, such as age-related osteoporosis.

Adult↗
PubMed1998

Molecular mechanism of action of fluoride on bone cells.

Fluoride is an effective anabolic agent to increase spinal bone density by increasing bone formation, and at therapeutically relevant (i.e., micromolar) concentrations, it stimulates bone cell proliferation and activities in vitro and in vivo. However, the fluoride therapy of osteoporosis has been controversial, in large part because of a lack of consistent antifracture efficacy. However, information regarding the molecular mechanism of action of fluoride may improve its optimum and correct usage and may disclose potential targets for the development of new second generation drugs that might have a better efficacy and safety profile. Accordingly, this review will address the molecular mechanisms of the osteogenic action of fluoride. In this regard, we and other workers have proposed two competing models, both of which involve the mitogen activated protein kinase (MAPK) mitogenic signal transduction pathway. Our model involves a fluoride inhibition of a unique fluoride-sensitive phosphotyrosine phosphatase (PTP) in osteoblasts, which results in a sustained increase in the tyrosine phosphorylation level of the key signaling proteins of the MAPK mitogenic transduction pathway, leading to the potentiation of the bone cell proliferation initiated by growth factors. The competing model proposes that fluoride acts in coordination with aluminum to form fluoroaluminate, which activates a pertussis toxin-sensitive Gi/o protein on bone cell membrane, leading to an activation of cellular protein tyrosine kinases (PTKs), which in turn leads to increases in the tyrosine phosphorylation of signaling proteins of the MAPK mitogenic signal transduction pathway, ultimately leading to a stimulation of cell proliferation. A benefit of our model, but not the other model, is that it accounts for all the unique properties of the osteogenic action of fluoride. These include the low effective fluoride dose, the skeletal tissue specificity, the requirement of PTK-activating growth factors, the sensitivity to changes in medium phosphate concentration, the preference for undifferentiated osteoblasts, and the involvement of the MAPK. Unlike fluoride, the mitogenic action of fluoroaluminate is not specific for skeletal cells. Moreover, the mitogenic action of fluoroaluminate shows several important, different characteristics than that of fluoride. Thus, it is likely that our model of a fluoride-sensitive PTP represents the actual molecular mechanism of the osteogenic action of fluoride.

Animals↗