Sutada Lotinun

Continuous parathyroid hormone induces cortical porosity in the rat: effects on bone turnover and mechanical properties.

We examined the time course effects of continuous PTH on cortical bone and mechanical properties. PTH increased cortical bone turnover and induced intracortical porosity with no deleterious effect on bone strength. Withdrawal of PTH increased maximum torque to failure and stiffness with no change in energy absorbed.

Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression

A mechanism explaining the differential skeletal effects of intermittent and continuous elevation of serum parathyroid hormone (PTH) remains elusive. Intermittent PTH increases bone formation and bone mass and is being investigated as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by osteomalacia, focal bone resorption, and peritrabecular bone marrow fibrosis. Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. Many of the beneficial as well as detrimental effects of the hormone appear to be mediated by osteoblast-derived growth factors. This hypothesis was tested using cDNA microgene arrays to compare gene expression in tibia of rats treated with continuous and pulsatile administration of PTH. These treatments result in differential expression of many genes, including growth factors. One of the genes whose steady-state mRNA levels was increased by continuous but not pulsatile administration was platelet-derived growth factor-A (PDGF-A). Administration of a PDGF-A antagonist greatly reduced bone resorption, osteomalacia, and bone marrow fibrosis in a rat model for hyperparathyroidism, suggesting that PDGF-A is a causative agent for this disease. These findings suggest that profiling changes in gene expression can help identify the metabolic pathways responsible for the skeletal responses to the hormone.

Dietary soy protein and isoflavones: minimal beneficial effects on bone and no effect on the reproductive tract of sexually mature ovariectomized Sprague-Dawley rats.

Objective: The present study was conducted to determine the effects of dietary soy protein and isoflavones on bone and the reproductive tract in the absence of the ovary. Design: Three-month-old Sprague-Dawley rats (n = 56) were either sham-operated or ovariectomized and then fed diets containing casein or soy protein ± isoflavone extract for 12 weeks. The amounts of casein, soy protein, and extract (per kg diet) in each group were as follows: (1) Ovariectomy, 200 g of casein; (2) Ovariectomy+low soy, 100 g of casein + 100 g of soy protein; (3) Ovariectomy+high soy, 200 g of soy protein; (4) Ovariectomy+low extract, 200 g of casein + 17.2 g of extract; (5) Ovariectomy+high extract, 200 g of casein + 34.4 g of extract; (6) Ovary intact, 200 g of casein; (7) Ovariectomy+estradiol-17β, 200 g of casein. Diet consumption, body weight, uterine weight, urine deoxypyridinoline, and bone mineral density of the femur and lumbar vertebrae were measured. The femur rigidity was evaluated by histomorphometry. The reproductive tract (uterus, vagina, and cervix) was studied histologically. Results: The Ovariectomy group showed significant increases in body weight, diet consumption, and deoxypyridinoline, decreases in uterine weight and bone mineral density, and negative changes in histomorphometry compared with the Ovary intact group. Neither soy protein nor extract diets abrogated these alterations, except for the Ovariectomy+high extract group that showed statistically significant positive changes in histomorphometric parameters. There were no histological differences in the reproductive tract among Ovariectomy, Ovariectomy+soy, and Ovariectomy+extract groups. The estradiol-17β replacement abrogated ovariectomy-induced alterations. Conclusion: Dietary intake of isoflavones by sexually mature ovariectomized rats has a minimal beneficial effect on bone with no effect on the reproductive tract.

Deletion of Membrane‐Bound Steel Factor Results in Osteopenia in Mice

To examine the functional role of membrane‐bound SLF, we evaluated the growing skeletons of WT and SLF mutant (Sl/Sld) mice that do not produce this protein using DXA, bone histomorphometry, cell culture, and flow cytometry. Deletion of membrane‐bound SLF delays bone growth, decreases bone mass and BMD, impairs osteoblast function, and increases osteoclast surface in young mice.

Comparative effects of long-term continuous release of 16α-hydroxyestrone and 17β-estradiol on bone, uterus, and serum cholesterol in ovariectomized adult rats

Abstract 16α-Hydroxyestrone (16α-OHE 1 ), an endogenous estrogen metabolite, is associated with increased bone density in postmenopausal women. This study was designed to evaluate the long-term activity of this metabolite on bone, uterus, and serum cholesterol in an animal model for postmenopausal bone loss. A preliminary dose–response study performed in weanling rats determined 2000 μg/kg/day to be the optimal dose of 16α-OHE 1 for studying estrogenic effect on bone. The long-term experiment was performed in 6-month-old animals that were either sham-operated or OVX. The OVX rats were implanted sc with 60-day continuous-release carrier, 17β-estradiol (E 2 ) (33 μg/kg/day) or 16α-OHE 1 pellets (2000 μg/kg/day). OVX decreased uterine weight, increased body weight, serum cholesterol, and all dynamic bone histomorphometric measurements in cortical and cancellous bone, and resulted in a 54% bone loss at the tibial metaphysis. E 2 completely prevented OVX-induced bone loss, suppressed bone turnover, and induced uterine hypertrophy and hypercholesterolemia. 16α-OHE 1 acted as an E 2 agonist on bone, suppressing bone formation and resorption. However, the estrogen metabolite lowered serum cholesterol and was only a partial E 2 agonist on uterine weight and epithelial cell height. These results suggest that 16α-OHE 1 is an estrogen agonist on bone and may be responsible, in part, for the cholesterol-lowering activity attributed to estrogen. As a consequence of its skeletal effects, older women who produce high levels of 16α-OHE 1 could have a lower risk for developing postmenopausal osteoporosis than women who produce less-active estrogen metabolites.

Loss of Gsα in osteocytes leads to osteopenia due to sclerostin induced suppression of osteoblast activity

The stimulatory subunit of G-protein, Gsα, acts as a secondary messenger of G-protein coupled receptors (GPCRs) that primarily activates cAMP-induced signaling. GPCRs, such as the parathyroid hormone receptor (PTHR), are critical regulators of bone formation as shown by number of genetic manipulation studies targeting early osteoblast lineage cells. In this study, we have examined the role of Gsα in osteocytes, the terminally differentiated and most abundant cells of the osteoblast lineage. Mice lacking the stimulatory subunit of G-proteins (Gsα) in osteocytes (DMP1-GsαKO) have significant decrease of both trabecular and cortical bone, as assessed by μCT. Histomorphometric analysis showed that the osteopenia was mostly driven by more than 90% decrease in osteoblast numbers and activity whereas osteoclasts were only slightly decreased. The decrease in osteoblast number was associated with a striking lack of endocortical osteoblasts. We have previously shown that loss of the stimulatory subunit of G-proteins (Gsα) in osteocytes in vitro or in vivo induces high expression of sclerostin. To determine if the increased sclerostin levels contributed to the decreased endosteal bone lining cells and osteopenia, we treated wild-type mice with recombinant sclerostin and the DMP1-GsαKO mice with anti-sclerostin antibody. Treatment of wild-type mice with 100 μg/kg sclerostin for 3-weeks significantly reduced the numbers of bone lining cells and led to osteopenia. Next, the DMP1-GsαKO and control littermates were treated with the anti-sclerostin antibody (25 mg/kg, 2 times per week) for 4-weeks. Upon the antibody treatment, the endocortical osteoblasts reappeared in the DMP1-GsαKO mice to a comparable level to that of the vehicle treated control littermates. In control mice, E11/gp38 positive osteocytes were observed in parallel with the endocortical osteoblasts with higher dendrite density towards the endocortical osteoblasts. In DMP1-GsαKO mice, E11/gp38 positive osteocytes were lacking dendrites and were randomly scattered throughout the bone matrix. After treatment with anti-sclerostin antibody, DMP1-GsαKO mice showed increased E11/gp38 positive osteocytes near the endosteal bone surface and endosteal osteoblasts. The anti-sclerostin antibody treatment proportionally increased the bone volume but it could not completely rescue the osteopenia in the DMP1-GsαKO mice. Taken together, this data suggests that Gsα signaling in osteocytes leads to osteopenia driven, at least in part, by increased secretion of sclerostin.