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  • Author: Toshitsugu Sugimoto x
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Masanori Kanatani, Toshitsugu Sugimoto, Hiroshi Kaji, Junichi Kano and Kazuo Chihara

Kanatani M, Sugimoto T, Kaji H, Kano J, Chihara K. Effects of 22-oxacalcitriol on bone metabolism in vitro: comparison with calcitriol. Eur J Endocrinol 1995;133:618–25. ISSN 0804–4643

22-Oxacalcitriol (OCT), a synthetic vitamin D3 analog, can mimic the ability of calcitriol to differentiate leukemia and skin cells, to enhance the immune response and to suppress parathyroid hormone secretion, but has much less calcemic activity than that of calcitriol. The mechanism of this selective action remains not fully understood, and the actions of OCT on bone metabolism are little known. The present study was, therefore, designed to investigate the effects of OCT and calcitriol on: the proliferation and functions of osteoblastic MC3T3-E1 cells; osteoclast-like cell formation from hemopoietic blast cells in the absence of stromal cells as well as from unfractionated bone cells in the presence of stromal cells; bone resorption; and the proliferation of MC3T3-E1 cells via monocytes. 22-Oxacalcitriol and calcitriol inhibited [3H]thymidine (TdR) incorporation, alkaline phosphatase activity and collagen synthesis of MC3T3-E1 cells to a similar degree. Both OCT (10−10–10−8 mol/l) and calcitriol significantly and similarly stimulated osteoclast-like cell formation from both hemopoietic blast cells and unfractionated bone cells. 22-Oxacalcitriol (10−10 and 10−8 mol/l) significantly stimulated bone resorption, although to a slightly lesser degree than did calcitriol. Human monocyte-conditioned medium (CM) significantly stimulated TdR incorporation into MC3T3-E1 cells. On the other hand, CM obtained from monocytes treated with calcitriol (10−10–10−8 mol/l) significantly inhibited TdR incorporation in a dose-related fashion, whereas CM obtained from monocytes treated with OCT (10−10–10−8 mol/l) significantly stimulated TdR incorporation in a dose-related fashion. Thus, the actions of OCT on osteoblasts, osteoclast precursor cells and mature osteoclasts, possibly via osteoblasts, are mostly similar to those of calcitriol in vitro. The low activity of OCT in mobilizing calcium from bone in vivo, therefore, appears to be due to some other factor. OCT and calcitriol differed only in their indirect effects on the proliferation of osteoblasts via monocytes, possibly through modulating the release from monocytes of local factors that affect bone remodelling.

Toshitsugu Sugimoto, Third Division, Department of Medicine, Kobe University School of Medicine, Kobe, Japan

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Makoto Arao, Toru Yamaguchi, Toshitsugu Sugimoto, Masaaki Fukase and Kazuo Chihara

Arao M, Yamaguchi T, Sugimoto T, Fukase M, Chihara K. Involvement of protein kinase C in sodiumdependent phosphate transport by parathyroid hormone in osteoblast-like cells. Eur J Endocrinol 1994;131:646–51. ISSN 0804–4643

The rat osteosarcoma cell line UMR-106 has an osteoblast-like phenotype and possesses parathyroid hormone (PTH)-responsive dual signal transduction systems [adenosine 3′,5′-cyclic monophosphatedependent protein kinase (PKA) and calcium-protein kinase C (Ca-PKC)]. These cells transport inorganic phosphate (Pi) by a Na+-dependent carrier under stimulation by PTH. The present study aimed to clarify PTH-responsive signal transduction mechanisms in the regulation of Na+-dependent Pi transport by PTH in UMR-106 cells. Exposure of these cells to 10−7 mol/l PTH induced a significant increase in Pi uptake within 30 min of incubation and it became maximal after 2 h. Parathyroid hormone (10−9 –10−7 mol/l) stimulated Pi uptake dose dependently. Activation of PKC by 12-O-tetradecanoyl phorbol- 13-acetate (TPA) also increased Pi uptake in time- and dose-dependent manners similar to PTH In contrast, neither PKA activation by 10 mol/l forskolin or by 10−4 mol/l dibutyryladenosine 3′,5′-cyclic monophosphate nor calcium ionophore treatment with 10−7 mol/l A23187 or with 10−7 mol/l ionomycin during 3-h incubations affect Pi uptake, except its increase by 10−4 mol/l forskolin at a 3-h incubation. These agents had no influence on Pi uptake even in combined treatments with TPA. The PTH-induced increase in Pi uptake was abolished almost completely by pretreating cells with PKC inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H-7) (50 μmol/l) or staurosporin (10 and 50 nmol/l), and by down-regulating PKC with a prolonged TPA treatment. These results indicate that the messenger system mediated by PKC, rather than by PKA or by cytosolic calcium, plays a crucial role in the regulation of Na+-dependent Pi transport by PTH within a few hours of exposure of the hormone in the osteoblast-like cells.

Toru Yamaguchi, Third Division, Department of Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650, Japan

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Hiroshi Kaji, Mika Yamauchi, Kazuo Chihara and Toshitsugu Sugimoto

Background and objective: Primary hyperparathyroidism (pHPT) is one of the causal diseases that induce secondary osteoporosis. Although patients with pHPT have reduced bone mineral density (BMD) especially at the cortical bone, there have been controversies about risk of fracture. Moreover, no reports have been available about the threshold of BMD for fractures in pHPT patients.

Methods: BMD values were measured by dual-energy x-ray absorptiometry at lumbar spine, femoral neck and distal one third of radius. Various indices were compared in 116 female pHPT patients and 716 control subjects. Moreover, we analyzed relationship between the cut-off values of BMD and the prevalence of vertebral fractures in pHPT and control subjects.

Results: The prevalence of subjects with vertebral fractures was lower in pHPT patients, compared with that of control subjects. Age and body height were significantly higher and lower in pHPT women with vertebral fractures, respectively. Lumbar spine BMD was significantly lower in pHPT women with vertebral fractures, presumably due to their increased age. There were no differences in femoral neck and radius BMD or in bone metabolic indices between pHPT women with and without vertebral fractures. On the other hand, age-matched BMD was not significantly different between both groups at any measured site. Cut-off values of BMD at lumbar spine and femoral neck were lower in postmenopausal pHPT patients, compared with those of the postmenopausal control group. Moreover, cut-off values of BMD at radius was much lower in postmenopausal pHPT patients, compared with those of the postmenopausal control group (pHPT vs control (g/cm2): 0.670 vs 0.706 at lumbar spine; 0.549 vs 0.570 at femoral; 0.394 vs 0.474 at radius). Sensitivity and specificity of vertebral fractures was lower in pHPT patients, compared with those in control group.

Conclusions: The present cross-sectional study demonstrated that thresholds of BMD for vertebral fractures were lower especially at radial bone in female patients with pHPT, compared with those in the control group.

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Masamichi Nasu, Toshitsugu Sugimoto, Mieko Chihara, Mitsuo Hiraumi, Fumihiko Kurimoto and Kazuo Chihara

Abstract

The present study was performed to examine the effect of natural menopause on serum levels of IGF-I, IGF-binding protein (IGFBP-2) and -3 as well as on bone mass and lipid metabolism in perimenopausal women. One hundred and twenty-one healthy Japanese women, who were 45–55 years old, were studied (71 premenopausal and 50 postmenopausal women 1–9 years after menopause). Bone mineral density (BMD) was measured at the middle third of the radius by using dual energy X-ray absorptiometry. Serum levels of IGF-I, but not those of IGFBP-2 or -3, were significantly reduced in the postmenopausal group compared with the premenopausal group. One year after menopause, serum IGF-I levels were significantly lower, and the biochemical markers of bone turnover, such as serum total alkaline phosphatase level and urinary calcium to creatinine ratio, were significantly higher than the premenopausal levels. Serum levels of IGF-I, but not those of IGFBP-2 or-3, were positively correlated with BMD. Serum levels of IGFBP-2, but not those of IGF-I or IGFBP-3, were negatively correlated with body mass index and body weight. Finally, serum levels of IGFBP-3, but not those of IGF-I, were positively correlated with serum levels of total cholesterol and triglyceride. The present findings suggest that a rapid decrease in serum IGF-I levels after menopause might be partly involved in bone loss following gonadal failure and that IGFBP-2 and -3 might be related to the regulation of body mass and lipid metabolism during perimenopause respectively, although the mechanisms remain unknown.

European Journal of Endocrinology 136 608–616

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Ippei Kanazawa, Toru Yamaguchi, Masahiro Yamamoto, Mika Yamauchi, Shozo Yano and Toshitsugu Sugimoto

Background

Although, adiponectin might be associated with bone metabolism, the relationships between serum adiponectin and bone mineral density (BMD) as well as vertebral fracture in type 2 diabetes are still unclear.

Objective and methods

We investigated the relationships between each of serum total and high molecular weight (HMW) adiponectin versus BMD, bone markers, and the presence of vertebral fractures in a total of 231 men and 170 post-menopausal women with type 2 diabetes.

Results

Multiple regression analysis adjusted for age, duration of diabetes, BMI, serum creatinine, and HbA1c showed that serum total adiponectin was negatively correlated with BMD at the total, lumbar spine, and femoral neck (r=−0.165, P<0.05; r=−0.187, P<0.05; and r=−0.136, P<0.05 respectively) and positively with urinary N-terminal cross-linked telopeptide of type-I collagen in men (r=0.148, P<0.05), and that serum HMW adiponectin was negatively correlated with BMD at the lumbar spine (r=−0.146, P<0.05). Multivariate logistic regression analysis adjusted for the parameters described above showed that total adiponectin was associated with the presence of vertebral fractures in men (odds ratio (OR)=1.396, 95% confidential interval (CI) 1.020–1.911 per s.d. increase, P<0.05), and both total and HMW adiponectin were associated with moderate or severe vertebral fractures (OR=1.709, 95% CI 1.048–2.787 per s.d. increase, P<0.05 and OR=1.810, 95% CI 1.112–2.946 per s.d. increase, P<0.05 respectively), but not in post-menopausal women.

Conclusions

Serum adiponectin could be associated with BMD and turnover and clinically useful for assessing the risk of vertebral fractures in type 2 diabetic men.

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Keisuke Kobayashi, Yasuo Imanishi, Akimitsu Miyauchi, Naoyoshi Onoda, Takehisa Kawata, Hideki Tahara, Hitoshi Goto, Takami Miki, Eiji Ishimura, Toshitsugu Sugimoto, Tetsuro Ishikawa, Masaaki Inaba and Yoshiki Nishizawa

Objective: While the importance of fibroblast growth factor (FGF)-23 is established in phosphate-wasting disorders, little is known about the mechanisms regulating its circulating level. To investigate the role of parathyroid hormone (PTH) and calcium in FGF-23 metabolism, we examined plasma FGF-23 levels in patients with primary hyperparathyroidism (PHPT).

Patients and methods: Fifty patients with PHPT and 52 controls were employed in this study. Plasma was obtained from 18 PHPT patients who underwent parathyroidectomy (PTX) on the first postoperative morning without vitamin D administration. Time-course samples were also obtained from 5 of 18 PTX patients without vitamin D analogs or calcium administration. The expression of Fgf23 on resected parathyroid glands was analyzed by reverse transcription (RT)–PCR and immunohistochemistry.

Results: FGF-23 was significantly elevated in PHPT patients compared with controls. FGF-23 levels were significantly correlated positively with serum corrected calcium and intact PTH levels, and negatively with creatinine clearance and inorganic phosphate, among which creatinine clearance and corrected calcium were independently associated factors. In 18 PTX patients, postoperative FGF-23 levels were significantly decreased compared with preoperative levels. Corrected-calcium levels were significantly decreased 1 h after PTX, and this was followed by a reduction in plasma FGF-23 levels in time-course study. In addition, postoperative FGF-23 levels in 18 PTX patients were significantly correlated with corrected calcium, consistent with a role of serum calcium as one of the major regulators of FGF-23. The absence of Fgf23 expression in parathyroid glands indicated that the parathyroid glands were not major sources of circulating FGF-23.

Conclusions: Serum calcium may regulate circulating FGF-23 levels in PHPT.