Sayuri Matsumoto

INCREASED IL-6 PRODUCTION BY CELLS ISOLATED FROM THE FIBROUS BONE DYSPLASIA TISSUES IN PATIENTS WITH MCCUNE-ALBRIGHT SYNDROME

McCune-Albright syndrome (MAS) is characterized by café-au-lait spot, multiple endocrine hyperfunction, and polyostotic fibrous dysplasia. A somatic point mutation of Gsalpha protein was reported to decrease GTPase activity, leading to increase in the GSalpha-associated hormone actions via cAMP. IL-6 is known to stimulate osteoclast formation and in the IL-6 promoter, a cAMP responsive element has been identified. In this paper, we investigated the role of IL-6 in the bone lesions of MAS, using the isolated fibrous cells from the polyostotic fibrous dysplasia tissues in bones of the two patients with MAS. Bone biopsy specimen revealed the increased osteoclast in number. In both patients, a GSalpha mutation (Arg201 -> His) was identified in the cultured fibrous cells. Intracellular cAMP content and IL-6 secretion by the patient cells were increased. Rp-8Br-cAMP significantly inhibited IL-6 production in the patient cells, while it had no effect on normal control. The addition of dibutyryl cAMP significantly increased the synthesis of IL-6 in normal control cells. In contrast, no effect of dibutyryl cAMP on IL-6 synthesis was observed in the cells from one of the MAS patients. These data suggest that IL-6 is, at least, one of the downstream effectors of cAMP and that the increased IL-6 synthesis has a pathogenic role in the bone lesions of MAS patients via increasing the number of osteoclasts. These results may provide a new strategy for the therapy of MAS patients.

Bone marrow-derived osteoclast-like cells from a patient with craniometaphyseal dysplasia lack expression of osteoclast-reactive vacuolar proton pump.

Craniometaphyseal dysplasia (CMD) is a rare craniotubular bone dysplasia transmitted in autosomal dominant or recessive form. This disease is characterized by cranial bone hyperostosis and deformity of the metaphyses of the long bones. Using osteoclast-like cells formed from patient bone marrow cells, we investigated the pathophysiology of CMD in a 3-yr-old patient. Untreated bone marrow cells from the patient differentiated into osteoclast-like cells in vitro. These cells were shown to have vitronectin beta-receptors using a specific monoclonal antibody, i.e., 23C6 (CD51), which reacts with osteoclasts in human bone biopsy samples. However, the number of these osteoclast-like cells formed from the patients bone marrow was only 40% of the normal controls. 1,25-dihydroxyvitamin-D3, bovine 1-34 parathyroid hormone, recombinant human interleukin-1 beta, recombinant human interleukin-6, or recombinant human macrophage colony-stimulating factor significantly increased, while salmon calcitonin significantly inhibited, the number of osteoclast-like cells. However, these cells could not resorb sperm whale dentin slices and lacked the osteoclast-reactive vacuolar proton pump as evidenced by a monoclonal antibody (E11). Western blot analysis using a monoclonal antibody to pp60c-src (327) revealed that protooncogene c-src expression by the platelets of the CMD patient was comparable to the normal control. These data suggest that: (a) the hyperostosis and the metaphyseal long bone deformity in the present CMD patient might be explained by osteoclast dysfunction due to impaired expression of the osteoclast-reactive vacuolar proton pump; and (b) a protooncogene c-src was not associated with the pathogenesis of the present CMD patient.

Interferon treatment on glomerulonephritis associated with hepatitis C virus

Abstract We report on a 10-year-old girl with glomerulonephritis associated with hepatitis C virus infection, who was treated with interferon-α. On the first renal biopsy at 8 years of age, mild mesangial hypercellularity in a segmental to semiglobal pattern was present in all glomeruli. After 6 months interferon-α therapy, proteinuria diminished completely. However, mesangial proliferation was advanced on the second biopsy at 10 years of age. We concluded that the interferon-α was effective in the treatment of proteinuria despite the lack of pathological improvement.

Hypophosphatemic Rickets Accompanying Congenital Microvillous Atrophy

This report concerns an 11‐year‐old boy who manifested hypophosphatemic rickets associated with congenital microvillous atrophy (CMA). He had been suffering from vomiting and severe diarrhea from the first day of life and had been treated with total parenteral nutrition (TPN) since he was 67 days old. At 4 years of age, intestinal biopsy resulted in a diagnosis of CMA. He was admitted to our hospital complaining of leg pain at the age of 11. Laboratory data revealed hypophosphatemia, elevated serum 1,25‐dihydroxyvitamin D (1,25(OH)2D) levels, and hypercalciuria. A roentgenogram showed rickets in the extremities. A balance study of phosphate in urine and stool indicated that the amount of phosphate leaking into the stool was greater than that into the urine. Moreover, the total amount of phosphate leaking from both the intestine and kidney exceeded the amount of phosphate intake from TPN. The rickets was healed by increasing the phosphate concentration in TPN. This case is different from X‐linked hypophosphatemic rickets but similar to hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in terms of hypercalciuria and elevated serum 1,25(OH)2D levels. The effectiveness of phosphate treatments used here is also similar to that used for HHRH. However, this type of hypophosphatemic rickets is unique in that phosphate leaking into the intestine plays an important role in its pathogenesis.

Long-term hospitalization during pregnancy is a risk factor for vitamin D deficiency in neonates

Abstract. In order to examine the effects of long-term hospitalization during pregnancy on vitamin D metabolism in pregnant women and neonates, we measured the serum 25-hydroxyvitamin D (25OHD) levels in pregnant women, as well as measuring 25OHD levels in cord blood and breast milk. In pregnant women hospitalized for longer than 1 month, the serum 25OHD levels were decreased at delivery compared with those in control subjects (10.9 ± 2.6 ng/l vs 19.5 ± 4.9 ng/l; P < 0.01). Although the levels of 25OHD in the cord blood were not significantly different between the long-term hospitalized and control pregnant women in this study (9.36 ± 1.7 ng/l vs 11.1 ± 3.0 ng/l), the 25OHD concentrations in the cord blood were significantly lower than the maternal levels in both groups; the ratios of the levels in cord blood to sera in the long-term hospitalized women and control subjects were 82.1% and 60.3%, respectively. Long maternal hospitalization does not always cause neonatal vitamin D deficiency, but could be one of its major risk factors. Therefore, sufficient sunlight exposure and intake of sufficient vitamin D are considered to be important to prevent vitamin D deficiency in long-term hospitalized pregrant women as well as their babies.

Treatment with recombinant IL-2 for recurrent respiratory infection in a case of cartilage-hair hypoplasia with autoimmune hemolytic anemia.

following an elevation of the soluble IL-2 receptor levels has been reported [6]. Although AIHA has been known as a complication of CHH [5,7], the mechanism by which CHH patients develop AIHA remains to be determined. In addition, soluble IL-2 receptor levels have not been investigated in CHH. We describe here a CHH patient with a remarkably short stature and severe immunodeficiency who received recombinant human IL-2 (rIL-2) for recurrent infections. The serum levels of IL-2 and soluble IL-2 receptor were determined to enable us to better understand immunodeficiency in CHH patients.

The role of IGF-I in phosphate therapy for the short stature of patients with hypophosphatemic vitamin D-resistant rickets

The role of phosphate in short-statured patients with X-linked hypophosphatemic rickets (XLH) was investigated. Plasma insulin-like growth factor (IGF)-I levels were within the normal range in XLH patients. After oral phosphate loading, plasma IGF-I levels increased clearly in XLH patients, while there were no changes in normal controls. Plasma IGF-I levels significantly correlated with the maximal serum parathyroid hormone (PTH) concentrations in XLH patients. Plasma PTH concentrations and nephrogenic cyclic AMP values were increased significantly in XLH patients compared with normal controls. The former values correlated significantly with the increments of serum phosphate concentrations. The increase of serum PTH concentrations did not correlate either with the decrease of serum calcium concentrations or with the serum 1,25-dihydroxyvitamin D concentrations in either XLH patients or the normal controls. A 1-34 human PTH loading test revealed a clear increase of the plasma IGF-I levels in two XLH patients, while there was no change in the normal controls. The height SD scores of XLH patients significantly correlated with the maximal increase of plasma IGF-I concentrations. These data suggest that the increased IGF-I levels via PTH were in part supposed to restore the IGF action resulting in improved growth in XLH patients due to phosphate therapy.