Biomedical subjects

Y Kasukawa

Publications and source records attributed to Y Kasukawa.

9 recordsLinked to original sources

PubMed2001

Evaluation of long-term sequential changes in bone mass and strength following withdrawal of incadronate disodium (YM175) in ovariectomized rats.

We evaluated the long-term effects of withdrawal of a newer third-generation bisphosphonate, incadronate disodium (YM175), on both cancellous and cortical bone mass and strength in ovariectomized (OVX) rats. One hundred and sixty female SD rats at 13 weeks of age were randomized into four groups: sham-operated, OVX, and low- and high- YM (0.01 or 0.1 mg/kg s.c., three times a week after OVX). After 4 weeks of treatment with vehicle or incadronate disodium, rats from each group (n = 8) were killed at 0 (baseline), 3, 6, 9, and 12 months after the withdrawal of YM175. Histomorphometric studies of the proximal tibia revealed a dose-dependent decrease in OVX-induced bone turnover; cancellous bone volume was significantly higher in the YM groups compared with the OVX control group up to 6 months after withdrawal at low dose and up to 12 months after withdrawal at high dose. The low-dose group showed little effect on tibial diaphyseal cortical bone volume and width, while the high-dose group preserved both cortical parameters 12 months after withdrawal. Mechanical testing of femurs revealed that both metaphyseal and diaphyseal strengths were significantly higher at high dose compared with the OVX group until 12 months after withdrawal. These observations demonstrated that high-dose incadronate disodium preserved both cancellous and cortical bone mass and strength in OVX rats for 12 months after withdrawal of the agent.

Animals↗

PubMed2001

Evidence that IGF-binding protein-5 functions as a growth factor.

Recent studies support the concept that IGF-binding protein-5 (IGFBP-5) stimulates bone formation, at least in part, via IGF-independent mechanisms. To evaluate this hypothesis further, we evaluated in vitro and in vivo effects of IGFBP-5 on bone formation parameters using the IGF-I knockout (KO) mouse. Treatment of serum-free cultures of osteoblast clones derived from IGF-I KO mice with recombinant human IGFBP-5 increased both proliferation and alkaline phosphatase (ALP) activity in a dose-dependent manner, an effect comparable to that seen with IGF-I. IGF-II levels from media conditioned by osteoblasts derived from IGF-I KO mouse were below those detectable by RIA. To eliminate possible actions of IGF-II, if any was produced by osteoblasts derived from IGF-I knockout mice, the IGFBP-5 effect was studied in the presence of exogenously added IGFBP-4, a potent inhibitor of IGF-II actions in bone cells. Addition of IGFBP-4 blocked IGF-I- but not IGFBP-5-induced cell proliferation in osteoblasts derived from IGF-I knockout mice. Consistent with in vitro results, a single local injection of IGFBP-5 to the outer periosteum of the parietal bone of IGF-I KO mice increased ALP activity and osteocalcin levels of calvarial bone extracts. The magnitudes of IGFBP-5-induced increases in ALP and osteocalcin in parietal bone extracts of IGF-I KO mice were comparable to those seen in C3H mice. In contrast to IGFBP-5, local administration of IGFBP-4 had no significant effect on bone formation in C3H and IGF-I KO mice. These results provide the first direct evidence to our knowledge that IGFBP-5 functions as a growth factor that stimulates its actions in part via an IGF-independent mechanism.

Alkaline Phosphatase↗

PubMed2001

Evidence that anabolic effects of PTH on bone require IGF-I in growing mice.

Although it has been established that PTH exerts potent anabolic effects on bone in animals and humans, the mechanism of PTH action on bone remains controversial. Based on the previous findings that PTH treatment increased production of IGF-I in bone cells and that PTH effects on bone cells in vitro were blocked by IGF-I-blocking antibodies, we proposed that IGF-I action is required for the stimulatory effects of PTH on bone formation. To test this hypothesis, we evaluated the effects of PTH on bone formation parameters in growing mice lacking functional IGF-I genes. Five-week-old IGF-I(-/-) mice and wild-type littermates were given daily sc injections of 160 microg/kg body weight of PTH (1-34) or vehicle for 10 d. In wild-type animals, PTH caused a significant increase in serum osteocalcin levels (113%), serum alkaline phosphatase activity (48%), and alkaline phosphatase activity in femoral bone extracts (>80%), compared with the vehicle-treated control group. In contrast, in IGF-I(-/-) mice, there was no significant effect of PTH on any bone formation parameters. PTH treatment increased total bone mineral density, as evaluated by peripheral quantitative computer tomography, at the distal metaphysis of the femur by 40% in wild-type mice, but it had no effect on bone mineral density in mice lacking functional IGF-I genes. In vitro studies using osteoblasts derived from control and IGF-I(-/-) mice revealed that PTH treatment increased cell number in osteoblasts derived from IGF-I knockout mice in the presence of exogenously added IGF-I but not without IGF-I. These data to our knowledge provide the first direct evidence that the anabolic effects of PTH on bone formation in vivo require IGF-I action in growing mice.

Animals↗

PubMed2001

Systemic administration of insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) increases bone formation parameters in mice by increasing IGF bioavailability via an IGFBP-4 protease-dependent mechanism.

Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) is a potent inhibitor of IGF actions in vitro. However, we found that systemic administration of IGFBP-4 at pharmacological doses caused a significant increase in bone formation parameters in mice by a mechanism that may involve increased IGF bioavailability via proteolysis of IGFBP-4. To evaluate the hypothesis that proteolysis of IGFBP-4 is essential for the stimulatory effects of systemically administered IGFBP-4, we produced wild-type, protease-resistant, and IGFBP-4 proteolytic fragments and evaluated their effects using biochemical markers. Protease-resistant IGFBP-4 was more potent than wild-type IGFBP-4 in inhibiting IGF-I-induced mouse osteoblast cell proliferation in vitro and in inhibiting IGF-I-induced increase in alkaline phosphatase (ALP) activity in bone extract after local administration in vivo. Systemic administration of wild-type IGFBP-4, but not protease-resistant IGFBP-4, increased serum osteocalcin, serum ALP, and ALP in skeletal extracts in a dose-dependent manner, with a maximal effect of 40% (P < 0.05) at 1.25 nmol/mouse. Systemic administration of wild-type, but not protease-resistant, IGFBP-4 increased free IGF-I levels in serum in normal mice. IGF-I, but not wild-type IGFBP-4, increased bone formation parameters in IGF-I-deficient mice. This study demonstrates that systemic administration of IGFBP-4 increases bone formation parameters in mice by increasing IGF bioavailability in the circulation via an IGFBP-4 protease-dependent mechanism.

Alkaline Phosphatase↗

PubMed2001

Long-term effects of withdrawal of bisphosphonate incadronate disodium (YM175) on bone mineral density, mass, structure, and turnover in the lumbar vertebrae of ovariectomized rats.

This study was designed to evaluate the long-term effects of incadronate disodium (YM175) after its withdrawal on cancellous bone mass in ovariectomized (OVX) rats. Thirteen-week-old female SD rats were randomized into four groups: sham-operated, OVX, low-YM, and high-YM (0.01 mg/kg or 0.1 mg/kg subcutaneously [sc], three times a week after OVX) groups. After 4 weeks of treatment with vehicle or YM175, rats from each group were killed at time points of 0 (baseline), 3, 6, 9, and 12 months after withdrawal of the agent. Bone mineral density (BMD) of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry (DXA). Bone volume (BV/TV), trabecular number and trabecular separation (Tb.N and Tb.Sp), eroded surface (ES/BS), osteoclast number and osteoclast surface (N.Oc/BS and Oc.S/BS), osteoid surface (OS/BS), and bone formation rate (BFR/BS) were measured as histomorphometric parameters of the fifth lumbar vertebra. BMD, BV/TV, Tb.N, and Tb.Sp in YM175-treated groups were maintained at the same level as in the sham group until 12 months after withdrawal in the high-YM group and until 3 months after withdrawal in the low-YM group. YM175 decreased both bone formative and resorptive parameters in histomorphometry. Serum bone-specific alkaline phosphatase (ALP) and urinary deoxypyridinoline at both doses of YM175 also showed a suppressive effect of this agent on bone turnover. These results indicate that YM175, after withdrawal, still maintains bone volume dose dependently by depressing bone resorption and formation in OVX rats. Intermittent YM175 treatment with a long interval may be sufficient to maintain the bone volume and structure in OVX rats.

Aging↗

PubMed2001

Restoring effect of human parathyroid hormone (1-34) on trabecular connectivity in ovariectomized rats.

The purpose of this study was to determine if the loss of the trabecular connectivities can be recovered by human parathyroid hormone-(1-34) therapy in ovariectomized (OVX) rats. Seven-month old female Wistar rats underwent ovariectomy or sham-operation at the beginning of the experiment. All sham operated groups (sham groups) were sacrificed after 0 (initial-BL group), 4, 8, 12, and 16 weeks, and one-third of the OVX rats were sacrificed as the baseline controls (OVX-BL groups) at 4, 8, and 12 weeks after OVX. Four weeks PTH or its vehicle treatment for residual OVX rats was started at 4, 8, or 12 weeks after OVX (OVX+PTH groups, OVX+vehicle groups). h-PTH (6.0 microg/kg) was injected subcutaneously six times a week for 4 weeks for each group. Their proximal right tibiae were processed for undecalcified Villanueva bone staining sections for bone histomorphometry. Furthermore, changes in trabecular connectivities were determined by node-strut analysis. h-PTH completely restored OVX-induced cancellous bone loss by stimulating bone formation. In node-strut analysis, node number in the OVX-BL-4, -8, and -12 groups was decreased to 53%, 49% and 44% of the initial-BL value respectively, and that in the OVX-4, -8, -12 + PTH groups recovered to 80%, 66%, 56% of the initial-BL value respectively. However, they were lower than those in their corresponding sham groups. The findings of this study suggested that decreased trabecular connectivity by OVX was recovered by intermittent h-PTH administration. However, delayed treatment blunted the restoration of trabecular connectivity.

Animals↗

PubMed2000

Histomorphometric evaluation of the recovering effect of human parathyroid hormone (1-34) on bone structure and turnover in streptozotocin-induced diabetic rats.

The purpose of this study was to determine whether human parathyroid hormone (h-PTH) enhances trabecular bone mass and connectivities that were reduced by streptozotocin (STZ)-induced diabetes in rats. Seven-month-old female Wistar rats were injected with STZ or its vehicle intraperitoneally. All vehicle-injected normal controls were sacrificed 0, 4, 6, 8, 12, 14, and 16 weeks after injection, and one-third of the STZ-injected rats were sacrificed as the baseline controls 4, 6, and 8 weeks after the injection. Eight-week h-PTH (6. 0 microg/kg, 6 times a week) or its vehicle treatment by subcutaneous injection for residual diabetic rats was started 4, 6, or 8 weeks after the STZ injection. The rats' proximal right tibiae were processed for undecalcified Villanueva bone staining sections for bone histomorphometry. Furthermore, changes in trabecular connectivities were determined by node-strut analysis. The decreased cancellous bone volume (BV/TV) and turnover in diabetic rats were recovered in all PTH-treated groups. In node-strut analysis, the node-related parameters (N.Nd/TV, NdNd/TV) were significantly increased by PTH when it was administered 4 weeks after STZ injection but were not increased when administration was started after 6 weeks. The results indicated that PTH enhanced bone turnover and bone mass but not trabecular connectivity in the late stage of diabetes in rats. Early treatment of osteoporosis is important in preventing fractures caused by decreased bone strength resulting from decreased trabecular connectivity.

Analysis of Variance↗

PubMed1999

Trabecular remodeling processes in the ovariectomized rat: modified node-strut analysis.

The purpose of this study was to evaluate the trabecular bone remodeling processes in ovariectomized rats, focusing on diminishing trabecular connectivity. We used modified node-strut analysis defining three areas in the trabecular surfaces for the three-dimensional understanding of trabecular resorption derived from two-dimensional conventional sections, in addition to conventional bone histomorphometry and node-strut analysis. Seven-month-old female Wistar rats were used and treated with bilateral ovariectomy (ovx) and sham operation. Six rats in each group were examined at 4 and 8 weeks. We prepared undecalcified sections from the left tibiae with Villanueva bone and Goldner stains. We divided the trabecular bone surfaces (BS) into three areas: node (Nd), terminus (Tm), and strut (St), and measured the bone resorption and formation parameters, including eroded surface (ES), osteoclast surface (Oc.S), osteoid surface (OS), and double-labeled surface (dLS) in each defined area. In conventional bone histomorphometry, the ovx group showed high turnover osteopenia compared with the sham operation group. In node-strut analysis, the ovx group showed significantly lower values for node-related parameters than did the sham operation group. In the modified node-strut analysis, bone resorption parameters in the ovx group showed significantly higher values, particularly for strut and terminus-eroded surfaces (StES/BS, TmES/BS), and for each area of osteoclast surface (NdOc.S/BS, TmOc.S/BS, and StOc.S/BS) compared with the sham operation group. Bone formation parameters in the ovx group also showed significantly higher values, particularly for strut and terminus osteoid surfaces (TmOS/BS, StOS/BS), and for each area of double-labeled surface (NddLS/BS, TmdLS/BS, and StdLS/BS) compared with the sham operation group at 4 weeks. At 8 weeks, each area of bone formation parameter in the ovx group showed significantly higher values than that in the sham operation group. These results suggest that in the ovx group, the trabecular plates became perforated and the perforative cavities progressively enlarged, and/or the edges of plates were eroded regardless of elevated bone formation, resulting in diminished trabecular connectivity, and the node area might not be influenced relatively by bone remodeling in the early resorption.

Animals↗

PubMed1999

Extra-abdominal desmoid tumor of the hand: a case report and review of the literature.

Extra-abdominal desmoid tumor of the hand is rare and only 10 cases have been described in the literature. We present a 14-year-old boy with a recurrent extra-abdominal desmoid tumor in the dorsal site of the right hand. MR image demonstrated the tumor in the third dorsal interosseous muscle, and adhered to the radial side of the forth metacarpal bone. The lesion revealed iso-signal intensity on T1-weighted images and high intensity on T2. We performed a marginal excision. Histological examination of the tumor showed proliferation of the fibroblastic cells with abundant collagen bundles. He developed local recurrence for the third time. The size of the third recurrent tumor has not been changed for 2 years and 3 months. Therefore, we have not performed any additional surgery. Since extensive resection markedly diminishes the function of the hand, we consider that a marginal surgical margin is acceptable for the quality of daily life of patients with a desmoid tumor of the hand.

Child↗