Circulating profiles of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand in post-menopausal women.

OBJECTIVE: The aim of this study was to elucidate the detail profiles of circulating osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) in post-menopausal women. METHODS: Eighty Japanese post-menopausal women were enrolled in this cross-sectional study. Circulating OPG and free fraction of sRANKL (free sRANKL), PTH, calcium and phosphorus, age, years since menopause, body mass index, bone mineral density of the vertebral bodies (LBMD) and bone turnover markers were determined in each subject. RESULTS: In rank order correlation analysis, serum OPG concentrations had a significant positive correlation with age (r=0.291, p=0.024) and a marginal significant negative correlation with LBMD (r=-0.247, p=0.062). However they did not have correlations with LBMD or other parameters after adjustment for age. Serum free sRANKL concentrations had a significant positive correlation with age (r=0.332, p=0.010) and a significant negative correlation with LBMD (r=-0.608, p<0.001). This correlation with LBMD persisted after adjustment for age. In a multiple regression analysis with a stepwise model, the main determinants of LBMD were age and serum free sRANKL (p=0.015 and p=0.006, respectively). CONCLUSIONS: We found the increase in circulating OPG and sRANKL with age and a robust negative correlation between circulating free sRANKL and LBMD after adjustment for age. The increase in circulating free sRANKL may reflect directly or indirectly the conditions coexistent with bone loss in post-menopausal women.

Association of serum undercarboxylated osteocalcin with serum estradiol in pre-, peri- and early post-menopausal women.

OBJECTIVE: We investigated changes in serum concentration of undercarboxylated osteocalcin (ucOC), which is a sensitive marker of vitamin K status, and association of ucOC concentration with estradiol concentration in pre-, peri- and early post-menopausal women. METHODS: The study population consisted of 193 pre-, peri- and post-menopausal Japanese women aged 39-66 yr. Serum ucOC concentration was measured to assess vitamin K status; serum concentrations of intact osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) were measured as bone formation markers; and urine concentration of N-telopeptide was measured as a bone resorption marker. Serum estradiol and estrone concentrations were measured by a highly sensitive radioimmunoassay. Bone mineral density (BMD) was measured at the lumbar spine. RESULTS: Serum concentration of ucOC in peri-menopausal women was significantly (p=0.0005) higher than that in pre-menopausal women, while serum OC concentration in post-menopausal women for whom 1 yr had passed since menopause was significantly (p=0.0003, p=0.024, respectively) higher than the concentrations in pre-menopausal and peri-menopausal women. Serum ucOC concentration showed a significant negative correlation with estradiol concentration (r=-0.372, p<0.0001) and a significant positive correlation with serum FSH concentration (r=0.324, p<0.0001). Serum OC concentration was positively correlated with serum FSH concentration (r=0.317, p<0.001). CONCLUSIONS: The results showed that the change in ucOC concentration during the menopausal transition is different from that in OC concentration. In addition, serum ucOC concentration is closely associated not only with FSH concentration but also estradiol concentration.

Induction of astroglial growth inhibition and differentiation by sialosyl cholesterol.

Normal rat astroblasts in culture were exposed to 11 sialosyl or cholesterol derivatives at concentrations lower than 20 microM. Synthesized sialosyl cholesterols (alpha- and beta-D-N-acetyl neuraminyl cholesterols) and cholesterol sulfate showed a marked growth inhibitory action. Sialosyl cholesterol uniquely evoked an astroglia-like stellation resembling that induced by glia maturation factor (GMF) as well as a suppression of GMF-induced mitogenesis of astroblasts. The minimal incubation period of sialosyl cholesterol for the initiation of growth inhibition was as short as one hour. The inhibitory effect retained an irreversibility even after removal of the drug. Cytosolic protein with 58 kDa Mr in size was specifically phosphorylated by sialosyl cholesterol through a certain protein kinase dependent on neither Ca2+ nor cyclic AMP. The competition experiment of sialosyl cholesterol action revealed that sialosyl and cholesterol moieties were indispensable for the phenomena. These results most likely imply that sialosyl cholesterol alters the membrane microenvironment to affect the affinity of growth factor receptor, protein kinase activity, and/or cytoskeletal anchorages.

RGS8 accelerates G-protein-mediated modulation of K+ currents.

Transmembrane signal transduction via heterotrimeric G proteins is reported to be inhibited by RGS (regulators of G-protein signalling) proteins. These RGS proteins work by increasing the GTPase activity of G protein alpha-subunits (G alpha), thereby driving G proteins into their inactive GDP-bound form. However, it is not known how RGS proteins regulate the kinetics of physiological responses that depend on G proteins. Here we report the isolation of a full-length complementary DNA encoding a neural-tissue-specific RGS protein, RGS8, and the determination of its function. We show that RGS8 binds preferentially to the alpha-subunits G(alpha)o and G(alpha)i3 and that it functions as a GTPase-activating protein (GAP). When co-expressed in Xenopus oocytes with a G-protein-coupled receptor and a G-protein-coupled inwardly rectifying K+ channel (GIRK1/2), RGS8 accelerated not only the turning off but also the turning on of the GIRK1/2 current upon receptor stimulation, without affecting the dose-response relationship. We conclude that RGS8 accelerates the modulation of G-protein-coupled channels and is not just a simple negative regulator. This property of RGS8 may be crucial for the rapid regulation of neuronal excitability upon stimulation of G-protein-coupled receptors.