Katsuhito Nishiyama

Serum Levels of Insulin-like Growth Factor (IGF) I, IGF-Binding Protein (IGFBP)-2, and IGFBP-3 in Osteoporotic Patients with and without Spinal Fractures

The present study was performed to investigate the role of insulin‐like growth factor I (IGF‐I), IGF‐binding protein‐2 (IGFBP‐2), and IGFBP‐3 in age‐dependent bone loss in postmenopausal Japanese women. One hundred and sixty‐five Japanese women aged 43–88 years (mean age, 62) were enrolled in the cross‐sectional study. Bone mineral density (BMD) was measured at the lumbar spine, femoral neck, and midradius by dual‐energy X‐ray absorptiometry or single‐photon absorptiometry. Serum levels of IGF‐I, IGFBP‐2, and IGFBP‐3 were measured by radioimmunoassay. BMD at all sites as well as serum levels of IGF‐I and IGFBP‐3 declined with age, while the serum IGFBP‐2 level increased with age. Serum IGFBP‐3 and −2 levels were positively and negatively correlated with the serum IGF‐I level, respectively. Serum IGF‐I and IGFBP‐3 levels showed positive correlationship with BMD at any site, particularly at the midradius, while the serum IGFBP‐2 level showed negative correlation with BMD. Multiple regression analyses showed age‐independent positive correlation between the serum IGF‐I level and BMD at all sites as well as age‐independent positive correlation between the serum IGFBP‐3 level and midradius BMD. The relationship between susceptibility to osteoporotic spinal fracture and serum IGF‐I, IGFBP‐3, or −2 levels was examined by decade to exclude the influence of aging. Serum levels of IGF‐I and IGFBP‐3 were significantly lower in subjects with spinal fractures than those without fractures at any decade. No significant difference of serum IGFBP‐2 level was observed between subjects with and without fractures. The present findings suggest that IGF‐I and IGFBP‐3 are important to maintaining bone mass quantitatively as well as qualitatively, and that the determination of serum IGF‐I and IGFBP‐3 levels could be clinically useful to predict the severity of osteoporosis, particularly the risk of bone fracture associated with osteoporosis.

Dexamethasone stimulates osteoclast-like cell formation by directly acting on hemopoietic blast cells and enhances osteoclast-like cell formation stimulated by parathyroid hormone and prostaglandin E2.

Although an excess of glucocorticoid induces secondary osteoporosis, the mechanism still remains unclear, particularly in regard to glucocorticoid‐stimulated bone resorption. We examined the effects of dexamethasone (Dex) on osteoclast‐like cell formation and bone‐resorbing activity by employing mouse bone and spleen cell cultures and further investigated whether Dex would modulate osteoclast‐like cell formation stimulated by several bone‐resorbing factors. Dex stimulated osteoclast‐like cell formation in stromal cell‐containing mouse bone cell cultures in a concentration‐dependent manner. Also, Dex significantly stimulated osteoclast‐like cell formation from hemopoietic blast cells in spleen cell cultures derived from 5‐fluorouracil‐pretreated mice. In contrast, Dex (10−8 M) did not affect the bone‐resorbing activity of mature osteoclasts. Pretreatment with 10−8 M Dex significantly enhanced osteoclast‐like cell formation in unfractionated mouse bone cell cultures stimulated by 10−8 M human (h) parathyroid hormone (PTH) (1–34), 10−8 M hPTH‐related protein (1–34) and 10−6 M prostaglandin E2, but not by 10−8 M 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3). Moreover, pretreatment with 10−8 M Dex significantly enhanced osteoclast‐like cell formation stimulated by both forskolin and dbcAMP. In contrast, pretreatment with 10−8 M Dex significantly inhibited osteoclast‐like cell formation in mouse spleen cell cultures stimulated by both 10−8 M hPTH(1–34) and 10−8 M 1,25(OH)2D3. These findings suggest that Dex stimulates osteoclast‐like cell formation, at least in part by directly acting on hemopoietic blast cells. They further suggest that Dex enhances osteoclast‐like cell formation stimulated by PTH and prostaglandin E2 through an indirect pathway via cells other than hemopoietic blast cells.

Insulin-like growth factor-I mediates osteoclast-like cell formation stimulated by parathyroid hormone.

There have been several lines of evidence that parathyroid hormone (PTH) stimulates production of insulinlike growth factor I (IGF‐I) in bone and that IGF‐I stimulates osteoclast formation. Thus, the present study was performed to clarify the possible role of IGF‐I in PTH‐stimulated osteoclastlike cell formation and the role of PTH‐responsive dual signal transduction systems (cyclic [c] AMP‐dependent protein kinase [PKA] and calcium/protein kinase C [PKC]) in its mechanism. Treatment with anti‐IGF‐I antibody (1–10 μg/ml) partially but significantly blocked hPTH‐(1‐34)‐stimulated osteoclastlike cell formation in unfractionated mouse bone cell cultures, although it did not affect osteoclastlike cell formation stimulated by 1,25‐dihydroxyvitamin D3. Rp‐cAMPS (10‐4 M), a direct PKA inhibitor, as well as two types of PKC inhibitors, H‐7 (10 μM) and staurosporine (3 nM), and dantrolene (10‐5 M), an inhibitor of calcium mobilization from intracellular calcium stores, all significantly blocked PTH‐stimulated osteoclastlike cell formation. Anti‐IGF‐I antibody (3 μg/ml) significantly blocked osteoclastlike cell formation stimulated by 10‐4 M dbcAMP, 10‐4 M Sp‐cAMPS, a direct PKA activator, and 10‐5 M forskolin in mouse bone cell cultures. Dibutyryl cAMP, forskolin, and hPTH‐(1‐34) significantly stimulated mRNA expression of both IGF‐I and IGF‐binding protein 5 (IGFBP‐5) in these cultures, but neither 10‐7 M PMA, a PKC activator, nor 10‐7 M A23187 did. Moreover, anti‐IGF‐I antibody significantly blocked osteoclastlike cell formation stimulated by the conditioned medium from MC3T3‐E1 cells pretreated with 10‐8 PTH‐(1‐34), which induced IGF‐I and IGFBP‐5 mRNA expression in these cells. In conclusion, the present study indicates that IGF‐I mediates osteoclastlike cell formation stimulated by PTH and that the PKA pathway is involved in its mechanism. However, IGF‐I does not seem to be the sole effector molecule to be active in this system. J. Cell. Physiol. 172:55–62, 1997.

Stimulatory Effect of Insulin-Like Growth Factor Binding Protein-5 on Mouse Osteoclast Formation and Osteoclastic Bone-Resorbing Activity

Insulin‐like growth factor binding protein‐5 (IGFBP‐5) stimulates osteoblast proliferation directly or indirectly through IGF‐I action, but its effects on osteoclast formation and osteoclastic activity are unknown. We tested the effects of IGFBP‐5 on osteoclastic activity and osteoclast formation. IGFBP‐5 significantly stimulated pit formation by pre‐existent osteoclasts in mouse bone cell cultures and its stimulatory effect was completely blocked by IGF‐I antibody (Ab). However, IGFBP‐5 did not affect the bone‐resorbing activity of isolated rabbit osteoclasts. When IGFBP‐5 was added to unfractionated bone cells after degeneration of pre‐existent osteoclasts, IGFBP‐5 (77 pM–7.7 nM) dose‐dependently stimulated osteoclast‐like cell formation, irrespective of the presence of IGF‐I Ab. Moreover, osteoclast‐like cells newly formed by IGFBP‐5 from unfractionated bone cells possessed the ability to form pits on dentine slices. We next examined the direct effect of IGFBP‐5 on osteoclast precursors in the absence of stromal cells, using hemopoietic blast cells derived from spleen cells. IGFBP‐5 dose‐dependently stimulated osteoclast‐like cell formation from osteoclast precursors, irrespective of the presence of IGF‐I Ab. Growth hormone (GH) as well as IGF‐I significantly stimulated bone resorption by pre‐existent osteoclasts in mouse bone cell cultures and these stimulatory effects were completely blocked by IGF‐I Ab. GH as well as IGF‐I stimulated osteoclast‐like cell formation from unfractionated bone cells and this stimulatory effect of GH was significantly but partially blocked by IGF‐I Ab. The direct stimulatory effect of GH on osteoclast‐like cell formation from hemopoietic blast cells was not affected by IGF‐I Ab. The present data indicate that IGFBP‐5 stimulates bone resorption both by stimulation of osteoclast formation in an IGF‐I–independent fashion and by IGF‐I–dependent activation of mature osteoclasts, possibly via osteoblasts, in vitro. (J Bone Miner Res 2000;15:902–910)

Incidence of fundic gland polyps in patients without familial adenomatous polyposis

The incidence of fundic gland polyps was evaluated using a high-resolution videoendoscope. In 1388 upper gastrointestinal endoscopic studies, 26 cases of fundic gland polyps (1.9% of the studied cases) were found. None of these patients had evidence of familial adenomatous polyposis. Fifteen of these patients (58%) had a solitary polyp in the gastric body, most of which were small sessile polyps of less than 2 mm in diameter. The results of this study indicated that a small solitary fundic gland polyp is not a rare gastric lesion and that little relationship exists between these solitary fundic gland polyps and familial adenomatous polyposis.

Fentanyl for sedation during upper gastrointestinal endoscopy

The effects of sedation by intravenous fentanyl on the rate-pressure product (pulse rate x systolic blood pressure/100), arterial oxygen saturation, electrocardiographic change, and serum cortisol concentration were studied during gastroduodenoscopy in 84 patients randomized to receive fentanyl or no intravenous sedative (controls). Fentanyl administration increased the tolerance of patients and attenuated the endoscopy-induced rise in rate-pressure product and serum cortisol concentration. Desaturation of arterial oxygen was minimal and there was no difference in arterial oxygen saturation between the fentanyl group and the control group. Therefore, fentanyl appears to be a favorable sedative for upper gastrointestinal endoscopy, since its administration increased the tolerance of patients and decreased cardiac oxygen consumption.

Arterial oxygen saturation, blood pressure, and pulse rate during upper gastrointestinal endoscopy — Influence of sedation and age

We studied the effect of sedation by I.V. meperidine on blood pressure, pulse rate, and arterial oxygen saturation during upper gastrointestinal endoscopy. Meperidine increased the tolerance of the patients and attenuated the endoscopy-induced rise in blood pressure and pulse rate. Arterial oxygen saturation was transiently depressed in the first few minutes of the endoscopic procedure even without sedation, and meperidine administration did not aggravate this oxygen desaturation. Therefore, meperidine may be a favorable sedative for upper gastrointestinal endoscopy because its treatment increases the tolerance of patients and decreases cardiac oxygen demand without decreasing arterial oxygen saturation.