[Pathophysiology and treatment of malignancy-associated hypercalcemia].
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Biomarkers↗
Biomedical subjects
Akimitsu Miyauchi
Publications and source records attributed to Akimitsu Miyauchi.
A paranasal tumor associated with tumor-induced osteomalacia.
BACKGROUND: Tumor-induced osteomalacia (TIO) is an extremely rare paraneoplastic syndrome associated with mesenchymal tumors in the craniofacial region. METHODS: We treated a 24-year-old Japanese woman with paranasal sinus tumor and a low serum phosphate level who presented with nasal obstruction and systemic bone fractures. Serum fibroblast growth factor 23 (FGF-23) was measured before and after surgery. RESULTS: After surgery, her symptoms were resolved and the serum phosphate and FGF-23 levels became normalized. CONCLUSION: FGF-23 is thought to be a useful diagnostic marker in patients with craniofacial tumors associated with multiple systemic fractures.
Adult↗
Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism.
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.
Calcium↗
Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia.
Fibrous dysplasia (FD) patients sometimes suffer from concomitant hypophosphatemic rickets/osteomalacia, resulting from renal phosphate wasting. It was recently reported that FD tissue in the patients with McCune-Albright syndrome (MAS) expressed fibroblast growth factor-23 (FGF-23), which is now known to be as a pathogenic phosphaturic factor in patients with oncogenic osteomalacia and X-linked hypophosphatemic rickets. Since it remains controversial whether serum phosphate levels are influenced by FGF23 expressions in FD tissue, isolated FD patients without MAS syndrome were examined for the relationship between FGF23 expressions, circulating levels of FGF-23 and phosphate to negate the effects of MAS-associated endocrine abnormalities on serum phosphate. Eighteen paraffin embedded FD tissues and 2 frozen tissues were obtained for the study. Sixteen of 18 isolated FD tissues were successfully analyzed GNAS gene, which exhibited activated mutations observed in MAS. Eight of 16 FD tissues, which exhibited GNAS mutations, revealed positive staining for FGF-23. These evidence indicate that postzygotic activated mutations of GNAS is necessary for the FD tissue formation by mosaic distribution of mutated osteogenic cell lineage, but is not sufficient to elevate FGF23 expression causing generalized osteomalacia with severe renal phosphate wasting. The expression level of FGF23 in isolated FD tissue with hypophosphatemic osteomalacia determined by real-time PCR was abundant close to the levels in OOM tumors. Osteoblasts/osteocytes in woven bone were predominant source of circulating FGF-23 in FD tissues by immunohistochemistry. A negative correlation of the intensity of FGF-23 staining with serum inorganic phosphate levels indicated that the expression of FGF23 in focal FD tissues could be a prominent determinant of serum phosphate levels in isolated FD patient. These data provide novel insights into the regulatory mechanism of serum inorganic phosphate levels in isolated FD patients and extend the notion that FGF-23 originating from FD tissue may cause hypophosphatemia not only in isolated FD patients but also in the patients with MAS syndrome.
Adolescent↗
Effect of age on body sway assessed by computerized posturography.
The swaying and postural instability frequently seen in elderly subjects had not been analyzed quantitatively in detail until the introduction of computerized posturography. In order to assess the changes of body sway with aging, we performed computerized posturography in 144 subjects (51 men and 93 women, between the ages of 22 and 88 years) without specific neurological or metabolic disorders. The total and timed track length of the center of gravity, reflecting the distance of sway, increased with advancing age, with a highly significant positive correlation, without marked sex differences. The total area covered by the track of the center of gravity (expressing the extent of sway) also showed a similar tendency. Track density per unit area, expressing the efficiency of postural control, in contrast, decreased with age, showing a significant negative correlation with age, but only when the subjects had their eyes open; this decrease did not occur when they had their eyes closed. The Romberg ratio, an index of exacerbation of sway on eye closure, showed little change with a tendency for slight alleviation of sway and improvement in the efficiency of its control. Computerized posturography appears to be a useful tool with which to analyze the mechanism of swaying associated with old age.
Adult↗
The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome.
McCune-Albright syndrome (MAS) is sometimes complicated by hypophosphatemia and abnormally low levels of 1,25(OH)(2)D in the presence of hypophosphatemia. Recently, fibroblast growth factor 23 (FGF-23) was reported as a phosphaturic and a causal factor of abnormal vitamin D metabolism. This abnormal phosphate and vitamin D metabolism is well known to be found in oncogenic and X-linked hypophosphatemia. We furthermore reported increased circulating plasma FGF-23 levels in patients with oncogenic and X-linked hypophosphatemia. To determine whether FGF-23 may be involved in the pathogenesis of MAS, we measured plasma FGF-23 levels in six MAS patients. As a control for hypophosphatemia, we also investigated the plasma FGF-23 levels in two patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We also investigated the correlation of plasma FGF-23 levels with serum phosphate and 1,25(OH)(2)D levels after short-term pamidronate therapy in three MAS patients. Plasma FGF-23 levels were significantly increased in patients with MAS compared to normal controls, whereas they were not increased in HHRH patients. Serum phosphate levels of the MAS patients were significantly lower than those observed in normal controls. Plasma FGF-23 levels showed significant negative correlation with serum phosphate concentrations. In three MAS patients, pamidronate therapy decreased plasma FGF-23 levels, which showed significant negative correlation with serum 1,25(OH)(2)D concentrations. These data suggested that FGF-23 is a possible causal factor for hypophosphatemia and abnormal vitamin D metabolism in MAS.
Adolescent↗
Reappraisal of Katsuragi calcium study, a prospective, double-blind, placebo-controlled study of the effect of active absorbable algal calcium (AAACa) on vertebral deformity and fracture.
A prospective, double-blind, placebo-controlled study of the effect of supplementation with 900 mg/day of calcium, as active absorbable algal calcium (AAA Ca) or calcium carbonate (CaCO(3)), on lumbar bone mineral density (BMD) carried out in elderly inpatients with osteoporosis at Katsuragi Hospital was re-evaluated in terms of the effects on vertebral fracture and spondylotic deformity. In addition to the already reported increase in lumbar BMD, AAA Ca was found to inhibit new occurrence of vertebral fracture. Intra-individual variations in L(1)-L(4) BMD (expressed by the coefficient of variation, indicating the degree of spondylotic deformity, were also inhibited significantly in the group supplemented with AAA Ca (group A), but not in group B (supplemented with CaCO(3)), from the level in the placebo-supplement group (group C) after 18 months of supple-mentation. According to whole-body dual-energy X-ray absorptiometry (DXA) results in the first and second year of the study, whole body mass, lean content, and mineral content, expressed as a percentage of whole body mass, stayed unchanged, while increase of fat content was significantly inhibited in group A, but not in group B, from the level in group C. As to the regional distribution of bone mineral content, the second year/first year value for head bone mineral content was significantly decreased with AAA supplementation compared with placebo, but no significant difference was found between CaCO(3) and placebo supplementation. Changes in mineral distribution in the arms, trunk, and legs showed no significant differences among the three groups. In addition to increasing BMD and preventing fracture, AAA Ca, but not CaCO(3), appears to inhibit the occurrence of spondylotic deformity and to decrease body fat content.
Absorptiometry, Photon↗
FGF-23 in patients with end-stage renal disease on hemodialysis.
BACKGROUND: Fibroblast growth factor (FGF)-23 is a recently identified circulating factor which causes renal phosphate wasting disorders. Although the mechanism of regulation of FGF-23 secretion is unknown, plasma FGF-23 level may be regulated or affected by serum phosphate levels because of its hypophosphatemic effect. METHODS: We tested the hypothesis that plasma FGF-23 levels may be increased in hyperphosphatemia in patients with end-stage renal disease (ESRD) on maintenance hemodialysis. We measured plasma FGF-23 levels in 158 male uremic patients on maintenance hemodialysis. Plasma samples were obtained before starting dialysis sessions to determine FGF-23 levels by enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma FGF-23 level exhibited significant and positive correlations with inorganic phosphate, intact parathyroid hormone (PTH), corrected calcium, and duration of hemodialysis on simple regression analyses. All these associations remained significant in multiple regression analyses. CONCLUSION: Serum phosphate, calcium, and intact PTH could be regulators of FGF-23 levels in uremic patients on maintenance hemodialysis. Our results may provide new insights into the pathophysiologic effects of FGF-23 on calcium-phosphate homeostasis.
Case-Control Studies↗
Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.
BACKGROUND: Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. METHODS: Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. RESULTS: Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. CONCLUSIONS: FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.
Adolescent↗
Intra-individual variation in lumbar bone mineral density as a measure of spondylotic deformity in the elderly.
In an attempt at quantitative assessment of spondylotic deformity, the intra-individual variation in L(1)-L(4) bone mineral density (BMD) was calculated, as the standard deviation (SD) and coefficient of variation (CV), obtained by dividing the SD by mean L(1)-L(4) BMD, in 463 subjects. The subjects ranged in age from their second to tenth decades. Dual-energy X-ray absorptiometry (DXA), using the Lunar DPX-L, was employed to assess the BMD. The SD of lumbar (L)BMD increased with advancing age in males, but not in females, whereas the CV of LBMD increased with age in both males and females, along with the radiographically assessed degree of severity of spondylosis deformans. Both the intra-individual SD and CV of L(1)-L(4) BMD showed a highly significant correlation with the radiological degree of severity of spondylosis deformans, and SD, but not CV, showed a strong dependence on the mean L(1)-L(4) BMD on a multiple regression test. Multiple regression test revealed no significant correlation between on body height, weight, fracture, and intra-individual variation in L(1)-L(4) projected area, reflecting compression fracture, one hand and SD or CV of L(1)-L(4) BMD on the other. Intra-individual variation in lumbar bone mineral density, expressed as a coefficient of variation, is suggested as an index of spondylotic deformity.
Adult↗
Distinct anabolic response of osteoblast to low-intensity pulsed ultrasound.
Low-intensity pulsed ultrasound, a form of mechanical energy transmitted as high-frequency acoustical pressure waves, provides noninvasive therapeutic treatment for accelerating fracture repair and distraction osteogenesis. Relatively young osteoblasts respond to ultrasound by transiently upregulating message levels of immediate-early genes as well as that of osteocalcin and insulin-like growth factor I (IGF-I). Osteocytes derived from newborn rat tibia and calvaria responded to a lesser extent only in c-fos and cyclooxygenase-2 (COX-2) messages. Compared with the stretched osteocytes, which use stretch-activated and parathyroid hormone (PTH)-potentiated Ca2+ influx as an entry route to the protein kinase A (PKA) signal transduction pathways, there was no evidence of Ca2+ internalization by any of the cells tested on exposure to the ultrasound. On the other hand, inhibitors of p38 mitogen-activated protein kinase (MAPK) and upstream phosphoinositide 3-kinase (PI3K) blocked COX-2 and osteocalcin upregulation by the ultrasound-exposed ST2, murine bone marrow-derived cells. This is distinct from the aforementioned osteocytic response to low-frequency stretching and implies the involvement of integrins. Our findings suggested that accelerated fracture repair and distraction osteogenesis by the low-intensity pulsed ultrasound depend, at least in part, on the stimulation of osteoblastic cells at relatively early stages of osteogenic lineage. Bone is under control of multiple regulatory mechanisms so that diverse physical forces can be reflected to the microenvironment of each cell, in turn, to the entire bone.
Animals↗
The effect of active absorbable algal calcium (AAA Ca) with collagen and other matrix components on back and joint pain and skin impedance.
The effect of active absorbable algal calcium (AAA Ca) with collagen and other matrix components on aging-associated skin changes and backache and joint pain was tested in a case-controlled study of 40 test subjects and 40 age-matched control subjects (mean age, 65 years) complaining of backache and knee joint pain due to osteoarthritis, spondylosis deformans, and/or osteoporosis. Supplementation with 900 mg calcium (given as AAA Ca) and 3.5 g collagen and other matrix components, including glucosamine, daily for 4 months resulted in a marked alleviation of subjective pain, assessed by the face scale. A fall of skin impedance in response to exercise loads, such as standing up, walking, squatting, and climbing up and down stairs, reported as an objective manifestion of pain, was also alleviated. The basal skin impedance, which increases with age, was significantly reduced in response to the Ca-collagen-matrix supplementation, suggesting a change of skin properties similar to rejuvenation, along with subjective smoothening and moistening of the skin. Urinary excretion of N-terminal crosslinking telopeptide of type I collagen (NTx) was decreased in the Ca-collagen-matrix supplementation group, but not in the control group. In addition to calcium suppression of parathyroid hormone, preventing bone resorption, collagen, acting on the intestinal lymphatic system, may protect collagen from degradation through the inhibition of cytokine-induced release of metalloproteinases, including collagenase.
Absorption↗
[Osteocytes and adhesion molecules].
Osteocytes, dendric resident cells in bone, transduce signals of mechanical loading that results in anabolic responses of bone. We have reported the involvement of stretch-activated Ca channels (SA-Cat) in this process. Besides, integrin receptors have been reported to function as mechanosensors. Osteocytes express some adhesion molecules, integrins and CD44, which could mediate signal transduction of mechanical stress as well as osteoblastic differentiation.
English Abstract↗